JP2007506726A - Method for using amino acids having affinity for α2δ-protein - Google Patents

Abstract

  The present invention relates to certain β-amino acids that bind to the alpha-2-delta (α2δ) subunit of calcium channels. These compounds and their pharmaceutically acceptable salts are useful for the treatment of various psychiatric, pain and other disorders.

Description

BACKGROUND OF THE INVENTION This invention relates to certain β-amino acids that bind to the alpha-2-delta (α2δ) subunit of calcium channels. These compounds and their pharmaceutically acceptable salts are useful for the treatment of various psychiatric, pain and other disorders.

（式中、Ｒ₁は、水素、または1〜5個のフッ素原子で任意に置換される（Ｃ₁〜Ｃ₆）アルキルであり；
Ｒ₂は、水素、または1〜5個のフッ素原子で任意に置換される（Ｃ₁〜Ｃ₆）アルキルであり；あるいは
Ｒ₁およびＲ₂は、それらが結合される炭素と一緒になって、３〜６員シクロアルキル環を形成し；
Ｒ₃は、（Ｃ₁〜Ｃ₆）アルキル、（Ｃ₃〜Ｃ₆）シクロアルキル、（Ｃ₃〜Ｃ₆）シクロアルキル−（Ｃ₁〜Ｃ₃）アルキル、フェニル、フェニル−（Ｃ₁〜Ｃ₃）アルキル、ピリジル、ピリジル−（Ｃ₁〜Ｃ₃）アルキル、フェニル−Ｎ（Ｈ）−、またはピリジル−Ｎ（Ｈ）−であり（ここで、前記アルキル部分は各々、1〜5個のフッ素原子で、好ましくは0〜3個のフッ素原子で任意に置換され得るし、そして前記フェニルおよび前記ピリジル、ならびに前記フェニル−（Ｃ₁〜Ｃ₃）アルキルおよび前記ピリジル−（Ｃ₁〜Ｃ₃）アルキルのフェニルおよびピリジル部分は、それぞれ、クロロ、フルオロ、アミノ、ニトロ、シアノ、（Ｃ₁〜Ｃ₃）アルキルアミノ、（Ｃ₁〜Ｃ₃）アルキル（1〜3個のフッ素原子で任意に置換される）、および（Ｃ₁〜Ｃ₃）アルコキシ（1〜3個のフッ素原子で任意に置換される）から独立して選択される1〜3個の置換基で、好ましくは0〜2個の置換基で任意に置換され得る）；
Ｒ₄は、水素、または（Ｃ₁〜Ｃ₆）アルキル（1〜5個のフッ素原子で任意に置換される）であり；
Ｒ₅は、水素、または（Ｃ₁〜Ｃ₆）アルキル（1〜5個のフッ素原子で任意に置換される）であり；そして
Ｒ₆は、水素または（Ｃ₁〜Ｃ₆）アルキルである）
の化合物、またはこのような化合物の製薬上許容可能な塩に関する。 SUMMARY OF THE INVENTION The present invention provides compounds of formula I:

Wherein R ₁ is hydrogen or (C ₁ -C ₆ ) alkyl optionally substituted with 1 to 5 fluorine atoms;
R ₂ is hydrogen or (C ₁ -C ₆ ) alkyl optionally substituted with 1 to 5 fluorine atoms; or R ₁ and R ₂ together with the carbon to which they are attached. Forming a 3-6 membered cycloalkyl ring;
R ₃ is (C ₁ -C ₆ ) alkyl, (C ₃ -C ₆ ) cycloalkyl, (C ₃ -C ₆ ) cycloalkyl- (C ₁ -C ₃ ) alkyl, phenyl, phenyl- (C _1- C ₃ ) alkyl, pyridyl, pyridyl- (C ₁ -C ₃ ) alkyl, phenyl-N (H)-, or pyridyl-N (H)-(wherein each alkyl moiety is 1-5 And optionally substituted with 0 to 3 fluorine atoms, and said phenyl and said pyridyl, and said phenyl- (C ₁ -C ₃ ) alkyl and said pyridyl- (C ₁ -C ₃₎ phenyl and pyridyl moieties of alkyl, respectively, chloro, fluoro, amino, nitro, cyano, (C ₁ -C ₃₎ alkylamino, optionally (C ₁ -C ₃₎ alkyl (1-3 fluorine atoms ), In and (C ₁ -C ₃₎ 1-3 substituents independently selected from alkoxy (optionally substituted with 1 to 3 fluorine atoms), preferably 0 to 2 substituents Can be optionally substituted);
R ₄ is hydrogen or (C ₁ -C ₆ ) alkyl (optionally substituted with 1 to 5 fluorine atoms);
R ₅ is hydrogen or (C ₁ -C ₆ ) alkyl (optionally substituted with 1 to 5 fluorine atoms); and R ₆ is hydrogen or (C ₁ -C ₆ ) alkyl. )
Or a pharmaceutically acceptable salt of such a compound.

Particular embodiments of the present invention include the following compounds of formula I and their pharmaceutically acceptable salts:
3-amino-5,8-dimethyl-nonanoic acid;
3-amino-5,5,7-trimethyl-octanoic acid;
3-amino-5,5,8-trimethyl-nonanoic acid;
3-amino-5,5,6-trimethyl-heptanoic acid;
(3S, 5S) -3-Amino-5,8-dimethyl-nonanoic acid;
(3S, 5R) -3-Amino-5,8-dimethyl-nonanoic acid;
(3S) -3-amino-5,5,6-trimethyl-heptanoic acid;
(3S) -3-amino-5,5,7-trimethyl-octanoic acid;
(3S) -3-amino-5,5,8-trimethyl-nonanoic acid; and (3S) -3-amino-5,5,9-trimethyl-decanoic acid.

Other examples of specific embodiments of the invention are the following compounds of formula I and their pharmaceutically acceptable salts:
3-amino-6-cyclobutyl-5-methyl-hexanoic acid;
3-amino-7-cyclopropyl-5-methyl-heptanoic acid;
3-amino-7-cyclobutyl-5-methyl-heptanoic acid;
3-Amino-7-cyclopentyl-5-methyl-heptanoic acid;
3-Amino-7-cyclohexyl-5-methyl-heptanoic acid;
3-amino-8-cyclopropyl-5-methyl-octanoic acid;
3-amino-8-cyclobutyl-5-methyl-octanoic acid;
3-amino-8-cyclopentyl-5-methyl-octanoic acid;
3-Amino-8-cyclohexyl-5-methyl-octanoic acid;
3-amino-6-cyclopropyl-5,5-dimethyl-hexanoic acid;
3-amino-6-cyclobutyl-5,5-dimethyl-hexanoic acid;
3-amino-6-cyclopentyl-5,5-dimethyl-hexanoic acid;
3-amino-6-cyclohexyl-5,5-dimethyl-hexanoic acid;
3-amino-7-cyclopropyl-5,5-dimethyl-heptanoic acid;
3-amino-7-cyclobutyl-5,5-dimethyl-heptanoic acid;
3-Amino-7-cyclopentyl-5,5-dimethyl-heptanoic acid;
3-Amino-7-cyclohexyl-5,5-dimethyl-heptanoic acid;

(3S, 5R) -3-Amino-6-cyclobutyl-5-methyl-hexanoic acid;
(3S, 5R) -3-Amino-7-cyclopropyl-5-methyl-heptanoic acid;
(3S, 5R) -3-Amino-7-cyclobutyl-5-methyl-heptanoic acid;
(3S, 5R) -3-Amino-7-cyclopentyl-5-methyl-heptanoic acid;
(3S, 5R) -3-Amino-7-cyclohexyl-5-methyl-heptanoic acid;
(3S, 5R) -3-Amino-8-cyclopropyl-5-methyl-octanoic acid;
(3S, 5R) -3-Amino-8-cyclobutyl-5-methyl-octanoic acid;
(3S, 5R) -3-Amino-8-cyclopentyl-5-methyl-octanoic acid;
(3S, 5R) -3-Amino-8-cyclohexyl-5-methyl-octanoic acid;
(3S, 5S) -3-Amino-6-cyclobutyl-5-methyl-hexanoic acid;
(3S, 5S) -3-Amino-7-cyclopropyl-5-methyl-heptanoic acid;
(3S, 5S) -3-Amino-7-cyclobutyl-5-methyl-heptanoic acid;
(3S, 5S) -3-Amino-7-cyclopentyl-5-methyl-heptanoic acid;
(3S, 5S) -3-Amino-7-cyclohexyl-5-methyl-heptanoic acid;
(3S, 5S) -3-Amino-8-cyclopropyl-5-methyl-octanoic acid;
(3S, 5S) -3-Amino-8-cyclobutyl-5-methyl-octanoic acid;
(3S, 5S) -3-Amino-8-cyclopentyl-5-methyl-octanoic acid;
(3S, 5S) -3-Amino-8-cyclohexyl-5-methyl-octanoic acid;
(3S) -3-amino-6-cyclopropyl-5,5-dimethyl-hexanoic acid;
(3S) -3-amino-6-cyclobutyl-5,5-dimethyl-hexanoic acid;
(3S) -3-amino-6-cyclopentyl-5,5-dimethyl-hexanoic acid;
(3S) -3-amino-6-cyclohexyl-5,5-dimethyl-hexanoic acid;
(3S) -3-Amino-7-cyclopropyl-5,5-dimethyl-heptanoic acid;
(3S) -3-Amino-7-cyclobutyl-5,5-dimethyl-heptanoic acid;
(3S) -3-amino-7-cyclopentyl-5,5-dimethyl-heptanoic acid; and (3S) -3-amino-7-cyclohexyl-5,5-dimethyl-heptanoic acid.

Other particular embodiments of the invention include the following compounds of formula I and their pharmaceutically acceptable salts:
3-amino-5-methyl-heptanoic acid;
3-amino-5-methyl-octanoic acid;
3-amino-5-methyl-nonanoic acid;
3-amino-5,5-dimethyl-nonanoic acid;
3-amino-5,5-dimethyl-decanoic acid;
(3S) -3-amino-5,5-dimethyl-nonanoic acid; and (3S) -3-amino-5,5-dimethyl-decanoic acid.

（式中、Ｒ₁は、水素、または1〜5個のフッ素原子で任意に置換される（Ｃ₁〜Ｃ₆）アルキルであり；
Ｒ₂は、水素、または1〜5個のフッ素原子で任意に置換される（Ｃ₁〜Ｃ₆）アルキルであり；あるいは
Ｒ₁およびＲ₂は、それらが結合される炭素と一緒になって、３〜６員シクロアルキル環を形成し；
Ｒ₃は、（Ｃ₁〜Ｃ₆）アルキル、（Ｃ₃〜Ｃ₆）シクロアルキル、（Ｃ₃〜Ｃ₆）シクロアルキル−（Ｃ₁〜Ｃ₃）アルキル、フェニル、フェニル−（Ｃ₁〜Ｃ₃）アルキル、ピリジル、ピリジル−（Ｃ₁〜Ｃ₃）アルキル、フェニル−Ｎ（Ｈ）−、またはピリジル−Ｎ（Ｈ）−であり（ここで、前記アルキル部分は各々、1〜5個のフッ素原子で、好ましくは0〜3個のフッ素原子で任意に置換され得るし、そして前記フェニルおよび前記ピリジル、ならびに前記フェニル−（Ｃ₁〜Ｃ₃）アルキルおよび前記ピリジル−（Ｃ₁〜Ｃ₃）アルキルのフェニルおよびピリジル部分は、それぞれ、クロロ、フルオロ、アミノ、ニトロ、シアノ、（Ｃ₁〜Ｃ₃）アルキルアミノ、（Ｃ₁〜Ｃ₃）アルキル（1〜3個のフッ素原子で任意に置換される）、および（Ｃ₁〜Ｃ₃）アルコキシ（1〜3個のフッ素原子で任意に置換される）から独立して選択される1〜3個の置換基で、好ましくは0〜2個の置換基で任意に置換され得る）；
但し、Ｒ₁が水素である場合、Ｒ₂は水素ではない）
の化合物、およびこのような化合物の製薬上許容可能な塩にも関する。 The present invention provides a compound of formula IA:

Wherein R ₁ is hydrogen or (C ₁ -C ₆ ) alkyl optionally substituted with 1 to 5 fluorine atoms;
R ₂ is hydrogen or (C ₁ -C ₆ ) alkyl optionally substituted with 1 to 5 fluorine atoms; or R ₁ and R ₂ together with the carbon to which they are attached. Forming a 3-6 membered cycloalkyl ring;
R ₃ is (C ₁ -C ₆ ) alkyl, (C ₃ -C ₆ ) cycloalkyl, (C ₃ -C ₆ ) cycloalkyl- (C ₁ -C ₃ ) alkyl, phenyl, phenyl- (C _1- C ₃ ) alkyl, pyridyl, pyridyl- (C ₁ -C ₃ ) alkyl, phenyl-N (H)-, or pyridyl-N (H)-(wherein each alkyl moiety is 1-5 And optionally substituted with 0 to 3 fluorine atoms, and said phenyl and said pyridyl, and said phenyl- (C ₁ -C ₃ ) alkyl and said pyridyl- (C ₁ -C ₃₎ phenyl and pyridyl moieties of alkyl, respectively, chloro, fluoro, amino, nitro, cyano, (C ₁ -C ₃₎ alkylamino, optionally (C ₁ -C ₃₎ alkyl (1-3 fluorine atoms ), In and (C ₁ -C ₃₎ 1-3 substituents independently selected from alkoxy (optionally substituted with 1 to 3 fluorine atoms), preferably 0 to 2 substituents Can be optionally substituted);
However, when R ₁ is hydrogen, R ₂ is not hydrogen)
And the pharmaceutically acceptable salts of such compounds.

（式中、Ｒは上記の式Ｉに関するのと同様に定義される）
の化合物、およびこのような化合物の製薬上許容可能な塩にも関する。 The present invention provides compounds of formula IA-1:

Wherein R is defined as for formula I above.
And the pharmaceutically acceptable salts of such compounds.

Other specific embodiments of the invention include the following compounds of formula IA and their pharmaceutically acceptable salts:
3-amino-5-methyl-8-phenylamino-octanoic acid;
3-amino-5-methyl-7-phenylamino-heptanoic acid;
3-amino-5-methyl-6-phenylamino-hexanoic acid;
(3S, 5R) -3-Amino-5-methyl-8-phenylamino-octanoic acid;
(3S, 5R) -3-Amino-5-methyl-7-phenylamino-heptanoic acid;
(3S, 5R) -3-Amino-5-methyl-6-phenylamino-hexanoic acid;
(3S, 5S) -3-Amino-5-methyl-8-phenylamino-octanoic acid;
(3S, 5S) -3-Amino-5-methyl-7-phenylamino-heptanoic acid;
(3S, 5S) -3-Amino-5-methyl-6-phenylamino-hexanoic acid;

3-amino-5-methyl-8-phenyl-octanoic acid;
3-Amino-8- (2-fluoro-phenyl) -5-methyl-octanoic acid;
3-Amino-8- (3-fluoro-phenyl) -5-methyl-octanoic acid;
3-Amino-8- (4-fluoro-phenyl) -5-methyl-octanoic acid;
3-Amino-8- (2-trifluoro-phenyl) -5-methyl-octanoic acid;
3-Amino-8- (3-trifluoro-phenyl) -5-methyl-octanoic acid;
3-Amino-8- (4-trifluoro-phenyl) -5-methyl-octanoic acid;
3-amino-5-methyl-8-o-tolyl-octanoic acid;
3-amino-5-methyl-8-m-tolyl-octanoic acid;
3-amino-5-methyl-8-p-tolyl-octanoic acid;
3-amino-5-methyl-8-p-tolyl-octanoic acid;
3-Amino-8- (2,3-difluoro-phenyl) -5-methyl-octanoic acid;
3-Amino-8- (2,4-difluoro-phenyl) -5-methyl-octanoic acid;
3-Amino-8- (2,5-difluoro-phenyl) -5-methyl-octanoic acid;
3-Amino-8- (2,6-difluoro-phenyl) -5-methyl-octanoic acid;

(3S, 5R) -3-Amino-5-methyl-8-phenyl-octanoic acid;
(3S, 5S) -3-Amino-5-methyl-8-phenyl-octanoic acid;
(3S, 5R) -3-Amino-8- (2-fluoro-phenyl) -5-methyl-octanoic acid;
(3S, 5S) -3-Amino-8- (2-fluoro-phenyl) -5-methyl-octanoic acid;
(3S, 5R) -3-Amino-8- (3-fluoro-phenyl) -5-methyl-octanoic acid;
(3S, 5S) -3-Amino-8- (3-fluoro-phenyl) -5-methyl-octanoic acid;
(3S, 5R) -3-Amino-8- (4-fluoro-phenyl) -5-methyl-octanoic acid;
(3S, 5S) -3-Amino-8- (4-fluoro-phenyl) -5-methyl-octanoic acid;
(3S, 5R) -3-Amino-8- (2-trifluoro-phenyl) -5-methyl-octanoic acid;
(3S, 5S) -3-Amino-8- (2-trifluoro-phenyl) -5-methyl-octanoic acid;
(3S, 5R) -3-Amino-8- (3-trifluoro-phenyl) -5-methyl-octanoic acid;
(3S, 5S) -3-Amino-8- (3-trifluoro-phenyl) -5-methyl-octanoic acid;
(3S, 5R) -3-Amino-8- (4-trifluoro-phenyl) -5-methyl-octanoic acid;
(3S, 5S) -3-Amino-8- (4-trifluoro-phenyl) -5-methyl-octanoic acid;
(3S, 5R) -3-Amino-5-methyl-8-o-tolyl-octanoic acid;
(3S, 5S) -3-Amino-5-methyl-8-o-tolyl-octanoic acid;
(3S, 5R) -3-Amino-5-methyl-8-m-tolyl-octanoic acid;
(3S, 5S) -3-Amino-5-methyl-8-m-tolyl-octanoic acid;
(3S, 5R) -3-Amino-5-methyl-8-p-tolyl-octanoic acid;
(3S, 5S) -3-Amino-5-methyl-8-p-tolyl-octanoic acid;
(3S, 5R) -3-Amino-8- (2,3-difluoro-phenyl) 5-methyl-octanoic acid;
(3S, 5S) -3-Amino-8- (2,3-difluoro-phenyl) 5-methyl-octanoic acid;
(3S, 5R) -3-Amino-8- (2,4-difluoro-phenyl) 5-methyl-octanoic acid;
(3S, 5S) -3-Amino-8- (2,4-difluoro-phenyl) 5-methyl-octanoic acid;
(3S, 5R) -3-Amino-8- (2,5-difluoro-phenyl) 5-methyl-octanoic acid;
(3S, 5S) -3-Amino-8- (2,5-difluoro-phenyl) 5-methyl-octanoic acid;
(3S, 5R) -3-amino-8- (2,6-difluoro-phenyl) 5-methyl-octanoic acid; and (3S, 5S) -3-amino-8- (2,6-difluoro-phenyl) 5-methyl-octanoic acid.

（式中、Ｒ₁、Ｒ₂およびＲ₃は上記の式Ｉに関するのと同様に定義される）
のものが挙げられる。 Preferred compounds of the invention include formula IA-2:

Wherein R ₁ , R ₂ and R ₃ are defined as for formula I above.
Can be mentioned.

Examples of further preferred compounds of the invention are compounds of formula IA-2, wherein R ₁ is hydrogen, R ₂ is methyl and R ₃ is defined as for formula I above.

Examples of specific embodiments of the present invention are the following compounds of formula IA-2 and pharmaceutically acceptable salts thereof:
(3S, 5R) -3-Amino-5-methyl-heptanoic acid;
(3S, 5R) -3-amino-5-methyl-octanoic acid; and (3S, 5R) -3-amino-5-methyl-nonanoic acid.

（式中、Ｒ₃は上記と同様である）
の化合物、およびそれらの製薬上許容可能な塩にも関し、そして上記の化合物は、以下の化合物およびそれらの製薬上許容可能な塩から選択される：
３−アミノ−４，５−ジメチル−ヘキサン酸；
３−アミノ−４，６−ジメチル−ヘプタン酸；
３−アミノ−４，７−ジメチル−オクタン酸；
３−アミノ−４，８−ジメチル−ノナン酸；
３−アミノ−４，９−ジメチル−デカン酸；
３−アミノ−４−シクロプロピル−ペンタン酸；
３−アミノ−４−シクロブチル−ペンタン酸；
３−アミノ−４−シクロペンチル−ペンタン酸；
３−アミノ−４−シクロヘキシル−ペンタン酸；
３−アミノ−５−シクロプロピル−４−メチル−ペンタン酸；
３−アミノ−５−シクロブチル−４−メチル−ペンタン酸；
３−アミノ−５−シクロペンチル−４−メチル−ペンタン酸；
３−アミノ−５−シクロヘキシル−４−メチル−ペンタン酸；
３−アミノ−６−シクロプロピル−４−メチル−ヘキサン酸；
３−アミノ−６−シクロブチル−４−メチル−ヘキサン酸；
３−アミノ−６−シクロペンチル−４−メチル−ヘキサン酸；
３−アミノ−６−シクロヘキシル−４−メチル−ヘキサン酸；
３−アミノ−７−シクロプロピル−４−メチル−ヘプタン酸；
３−アミノ−７−シクロブチル−４−メチル−ヘプタン酸；
３−アミノ−７−シクロペンチル−４−メチル−ヘプタン酸；
３−アミノ−７−シクロヘキシル−４−メチル−ヘプタン酸； The present invention provides a compound of formula IB:

(Wherein R ₃ is the same as above)
And the above-mentioned compounds are selected from the following compounds and their pharmaceutically acceptable salts:
3-amino-4,5-dimethyl-hexanoic acid;
3-amino-4,6-dimethyl-heptanoic acid;
3-amino-4,7-dimethyl-octanoic acid;
3-amino-4,8-dimethyl-nonanoic acid;
3-amino-4,9-dimethyl-decanoic acid;
3-amino-4-cyclopropyl-pentanoic acid;
3-amino-4-cyclobutyl-pentanoic acid;
3-amino-4-cyclopentyl-pentanoic acid;
3-amino-4-cyclohexyl-pentanoic acid;
3-amino-5-cyclopropyl-4-methyl-pentanoic acid;
3-amino-5-cyclobutyl-4-methyl-pentanoic acid;
3-amino-5-cyclopentyl-4-methyl-pentanoic acid;
3-amino-5-cyclohexyl-4-methyl-pentanoic acid;
3-amino-6-cyclopropyl-4-methyl-hexanoic acid;
3-amino-6-cyclobutyl-4-methyl-hexanoic acid;
3-amino-6-cyclopentyl-4-methyl-hexanoic acid;
3-amino-6-cyclohexyl-4-methyl-hexanoic acid;
3-amino-7-cyclopropyl-4-methyl-heptanoic acid;
3-amino-7-cyclobutyl-4-methyl-heptanoic acid;
3-amino-7-cyclopentyl-4-methyl-heptanoic acid;
3-Amino-7-cyclohexyl-4-methyl-heptanoic acid;

3-amino-8-cyclopropyl-4-methyl-octanoic acid;
3-amino-8-cyclobutyl-4-methyl-octanoic acid;
3-Amino-8-cyclopentyl-4-methyl-octanoic acid;
3-Amino-8-cyclohexyl-4-methyl-octanoic acid;
3-Amino-9-cyclopropyl-4-methyl-nonanoic acid;
3-Amino-9-cyclobutyl-4-methyl-nonanoic acid;
3-Amino-9-cyclopentyl-4-methyl-nonanoic acid;
3-amino-9-cyclohexyl-4-methyl-nonanoic acid;
3-amino-4-methyl-octanoic acid;
3-amino-4-methyl-nonanoic acid;
3-amino-4-methyl-decanoic acid;

(3R, 4R) -3-amino-4,5-dimethyl-hexanoic acid;
(3R, 4R) -3-amino-4,6-dimethyl-heptanoic acid;
(3R, 4R) -3-Amino-4,7-dimethyl-octanoic acid;
(3R, 4R) -3-Amino-4,8-dimethyl-nonanoic acid;
(3R, 4R) -3-Amino-4,9-dimethyl-decanoic acid;
(3R, 4R) -3-Amino-4-cyclopropyl-pentanoic acid;
(3R, 4R) -3-Amino-4-cyclobutyl-pentanoic acid;
(3R, 4R) -3-Amino-4-cyclopentyl-pentanoic acid;
(3R, 4R) -3-Amino-4-cyclohexyl-pentanoic acid;
(3R, 4R) -3-Amino-5-cyclopropyl-4-methyl-pentanoic acid;
(3R, 4R) -3-Amino-5-cyclobutyl-4-methyl-pentanoic acid;
(3R, 4R) -3-Amino-5-cyclopentyl-4-methyl-pentanoic acid;

(3R, 4R) -3-Amino-5-cyclohexyl-4-methyl-pentanoic acid;
(3R, 4R) -3-Amino-6-cyclopropyl-4-methyl-hexanoic acid;
(3R, 4R) -3-Amino-6-cyclobutyl-4-methyl-hexanoic acid;
(3R, 4R) -3-Amino-6-cyclopentyl-4-methyl-hexanoic acid;
(3R, 4R) -3-Amino-6-cyclohexyl-4-methyl-hexanoic acid;
(3R, 4R) -3-Amino-7-cyclopropyl-4-methyl-heptanoic acid;
(3R, 4R) -3-Amino-7-cyclobutyl-4-methyl-heptanoic acid;
(3R, 4R) -3-Amino-7-cyclopentyl-4-methyl-heptanoic acid;
(3R, 4R) -3-Amino-7-cyclohexyl-4-methyl-heptanoic acid;
(3R, 4R) -3-Amino-8-cyclopropyl-4-methyl-octanoic acid;
(3R, 4R) -3-Amino-8-cyclobutyl-4-methyl-octanoic acid;
(3R, 4R) -3-Amino-8-cyclopentyl-4-methyl-octanoic acid;

(3R, 4R) -3-Amino-8-cyclohexyl-4-methyl-octanoic acid;
(3R, 4R) -3-Amino-9-cyclopropyl-4-methyl-nonanoic acid;
(3R, 4R) -3-Amino-9-cyclobutyl-4-methyl-nonanoic acid;
(3R, 4R) -3-Amino-9-cyclopentyl-4-methyl-nonanoic acid;
(3R, 4R) -3-Amino-9-cyclohexyl-4-methyl-nonanoic acid;
(3R, 4R) -3-Amino-4-methyl-octanoic acid;
(3R, 4R) -3-Amino-4-methyl-nonanoic acid;
(3R, 4R) -3-Amino-4-methyl-decanoic acid;

(3R, 4S) -3-amino-4,5-dimethyl-hexanoic acid;
(3R, 4S) -3-amino-4,6-dimethyl-heptanoic acid;
(3R, 4S) -3-Amino-4,7-dimethyl-octanoic acid;
(3R, 4S) -3-Amino-4,8-dimethyl-nonanoic acid;
(3R, 4S) -3-Amino-4,9-dimethyl-decanoic acid;
(3R, 4S) -3-Amino-4-cyclopropyl-pentanoic acid;
(3R, 4S) -3-Amino-4-cyclobutyl-pentanoic acid;
(3R, 4S) -3-Amino-4-cyclopentyl-pentanoic acid;
(3R, 4S) -3-Amino-4-cyclohexyl-pentanoic acid;

(3R, 4S) -3-Amino-5-cyclopropyl-4-methyl-pentanoic acid;
(3R, 4S) -3-Amino-5-cyclobutyl-4-methyl-pentanoic acid;
(3R, 4S) -3-Amino-5-cyclopentyl-4-methyl-pentanoic acid;
(3R, 4S) -3-Amino-5-cyclohexyl-4-methyl-pentanoic acid;
(3R, 4S) -3-Amino-6-cyclopropyl-4-methyl-hexanoic acid;
(3R, 4S) -3-Amino-6-cyclobutyl-4-methyl-hexanoic acid;
(3R, 4S) -3-Amino-6-cyclopentyl-4-methyl-hexanoic acid;
(3R, 4S) -3-Amino-6-cyclohexyl-4-methyl-hexanoic acid;
(3R, 4S) -3-Amino-7-cyclopropyl-4-methyl-heptanoic acid;
(3R, 4S) -3-Amino-7-cyclobutyl-4-methyl-heptanoic acid;
(3R, 4S) -3-Amino-7-cyclopentyl-4-methyl-heptanoic acid;
(3R, 4S) -3-Amino-7-cyclohexyl-4-methyl-heptanoic acid;
(3R, 4S) -3-Amino-8-cyclopropyl-4-methyl-octanoic acid;
(3R, 4S) -3-Amino-8-cyclobutyl-4-methyl-octanoic acid;
(3R, 4S) -3-Amino-8-cyclopentyl-4-methyl-octanoic acid;
(3R, 4S) -3-Amino-8-cyclohexyl-4-methyl-octanoic acid;
(3R, 4S) -3-Amino-9-cyclopropyl-4-methyl-nonanoic acid;
(3R, 4S) -3-Amino-9-cyclobutyl-4-methyl-nonanoic acid;
(3R, 4S) -3-Amino-9-cyclopentyl-4-methyl-nonanoic acid;
(3R, 4S) -3-Amino-9-cyclohexyl-4-methyl-nonanoic acid;
(3R, 4S) -3-Amino-4-methyl-octanoic acid;
(3R, 4S) -3-amino-4-methyl-nonanoic acid; and (3R, 4S) -3-amino-4-methyl-decanoic acid.

（式中、Ｒ₃は上記と同様である）
の化合物、およびそれらの製薬上許容可能な塩にも関し、上記化合物は、以下の化合物およびそれらの製薬上許容可能な塩から選択される：
３−アミノ−６−メチル−デカン酸；
３−アミノ−６−シクロプロピル−ヘプタン酸；
３−アミノ−６−シクロブチル−ヘプタン酸；
３−アミノ−６−シクロペンチル−ヘプタン酸；
３−アミノ−６−シクロヘキシル−ヘプタン酸；
３−アミノ−７−シクロプロピル−６−メチル−ヘプタン酸；
３−アミノ−７−シクロブチル−６−メチル−ヘプタン酸；
３−アミノ−７−シクロペンチル−６−メチル−ヘプタン酸；
３−アミノ−７−シクロヘキシル−６−メチル−ヘプタン酸；
３−アミノ−８−シクロプロピル−６−メチル−オクタン酸；
３−アミノ−８−シクロブチル−６−メチル−オクタン酸；
３−アミノ−８−シクロペンチル−６−メチル−オクタン酸；
３−アミノ−８−シクロヘキシル−６−メチル−オクタン酸；
３−アミノ−９−シクロプロピル−６−メチル−ノナン酸；
３−アミノ−９−シクロブチル−６−メチル−ノナン酸；
３−アミノ−９−シクロペンチル−６−メチル−ノナン酸；
３−アミノ−９−シクロヘキシル−６−メチル−ノナン酸；
３−アミノ−１０−シクロプロピル−６−メチル−デカン酸；
３−アミノ−１０−シクロブチル−６−メチル−デカン酸；
３−アミノ−１０−シクロペンチル−６−メチル−デカン酸；
３−アミノ−１０−シクロヘキシル−６−メチル−デカン酸； The present invention provides a compound of formula IC:

(Wherein R ₃ is the same as above)
And the pharmaceutically acceptable salts thereof, the compound is selected from the following compounds and pharmaceutically acceptable salts thereof:
3-amino-6-methyl-decanoic acid;
3-amino-6-cyclopropyl-heptanoic acid;
3-amino-6-cyclobutyl-heptanoic acid;
3-amino-6-cyclopentyl-heptanoic acid;
3-amino-6-cyclohexyl-heptanoic acid;
3-amino-7-cyclopropyl-6-methyl-heptanoic acid;
3-amino-7-cyclobutyl-6-methyl-heptanoic acid;
3-amino-7-cyclopentyl-6-methyl-heptanoic acid;
3-Amino-7-cyclohexyl-6-methyl-heptanoic acid;
3-amino-8-cyclopropyl-6-methyl-octanoic acid;
3-amino-8-cyclobutyl-6-methyl-octanoic acid;
3-Amino-8-cyclopentyl-6-methyl-octanoic acid;
3-Amino-8-cyclohexyl-6-methyl-octanoic acid;
3-amino-9-cyclopropyl-6-methyl-nonanoic acid;
3-amino-9-cyclobutyl-6-methyl-nonanoic acid;
3-Amino-9-cyclopentyl-6-methyl-nonanoic acid;
3-Amino-9-cyclohexyl-6-methyl-nonanoic acid;
3-amino-10-cyclopropyl-6-methyl-decanoic acid;
3-amino-10-cyclobutyl-6-methyl-decanoic acid;
3-Amino-10-cyclopentyl-6-methyl-decanoic acid;
3-Amino-10-cyclohexyl-6-methyl-decanoic acid;

3-amino-6-isopropyl-heptanoic acid;
3-amino-6,8-dimethyl-nonanoic acid;
3-amino-6,9-dimethyl-decanoic acid;
(3S, 6R) -3-Amino-6-methyl-decanoic acid;
(3S, 6R) -3-Amino-6-cyclopropyl-heptanoic acid;
(3S, 6R) -3-Amino-6-cyclobutyl-heptanoic acid;
(3S, 6R) -3-Amino-6-cyclopentyl-heptanoic acid;
(3S, 6R) -3-Amino-6-cyclohexyl-heptanoic acid;

(3S, 6R) -3-Amino-7-cyclopropyl-6-methyl-heptanoic acid;
(3S, 6R) -3-Amino-7-cyclobutyl-6-methyl-heptanoic acid;
(3S, 6R) -3-Amino-7-cyclopentyl-6-methyl-heptanoic acid;
(3S, 6R) -3-Amino-7-cyclohexyl-6-methyl-heptanoic acid;
(3S, 6R) -3-Amino-8-cyclopropyl-6-methyl-octanoic acid;
(3S, 6R) -3-Amino-8-cyclobutyl-6-methyl-octanoic acid;
(3S, 6R) -3-Amino-8-cyclopentyl-6-methyl-octanoic acid;
(3S, 6R) -3-Amino-8-cyclohexyl-6-methyl-octanoic acid;
(3S, 6R) -3-Amino-9-cyclopropyl-6-methyl-nonanoic acid;
(3S, 6R) -3-Amino-9-cyclobutyl-6-methyl-nonanoic acid;
(3S, 6R) -3-Amino-9-cyclopentyl-6-methyl-nonanoic acid;
(3S, 6R) -3-Amino-9-cyclohexyl-6-methyl-nonanoic acid;
(3S, 6R) -3-Amino-10-cyclopropyl-6-methyl-decanoic acid;
(3S, 6R) -3-Amino-10-cyclobutyl-6-methyl-decanoic acid;
(3S, 6R) -3-Amino-10-cyclopentyl-6-methyl-decanoic acid;
(3S, 6R) -3-Amino-10-cyclohexyl-6-methyl-decanoic acid;

(3S, 6R) -3-Amino-6-isopropyl-heptanoic acid;
(3S, 6R) -3-Amino-6,8-dimethyl-nonanoic acid;
(3S, 6R) -3-Amino-6,9-dimethyl-decanoic acid;
(3S, 6S) -3-Amino-6-methyl-octanoic acid;
(3S, 6S) -3-Amino-6-methyl-nonanoic acid;
(3S, 6S) -3-Amino-6-methyl-decanoic acid;
(3S, 6S) -3-Amino-6-cyclopropyl-heptanoic acid;
(3S, 6S) -3-Amino-6-cyclobutyl-heptanoic acid;
(3S, 6S) -3-Amino-6-cyclopentyl-heptanoic acid;
(3S, 6S) -3-Amino-6-cyclohexyl-heptanoic acid;

(3S, 6S) -3-Amino-7-cyclopropyl-6-methyl-heptanoic acid;
(3S, 6S) -3-Amino-7-cyclobutyl-6-methyl-heptanoic acid;
(3S, 6S) -3-Amino-7-cyclopentyl-6-methyl-heptanoic acid;
(3S, 6S) -3-Amino-7-cyclohexyl-6-methyl-heptanoic acid;
(3S, 6S) -3-Amino-8-cyclopropyl-6-methyl-octanoic acid;
(3S, 6S) -3-Amino-8-cyclobutyl-6-methyl-octanoic acid;
(3S, 6S) -3-Amino-8-cyclopentyl-6-methyl-octanoic acid;
(3S, 6S) -3-Amino-8-cyclohexyl-6-methyl-octanoic acid;
(3S, 6S) -3-Amino-9-cyclopropyl-6-methyl-nonanoic acid;
(3S, 6S) -3-Amino-9-cyclobutyl-6-methyl-nonanoic acid;
(3S, 6S) -3-Amino-9-cyclopentyl-6-methyl-nonanoic acid;
(3S, 6S) -3-Amino-9-cyclohexyl-6-methyl-nonanoic acid;
(3S, 6S) -3-Amino-10-cyclopropyl-6-methyl-decanoic acid;
(3S, 6S) -3-Amino-10-cyclobutyl-6-methyl-decanoic acid;
(3S, 6S) -3-Amino-10-cyclopentyl-6-methyl-decanoic acid;
(3S, 6S) -3-Amino-10-cyclohexyl-6-methyl-decanoic acid;
(3S, 6S) -3-Amino-6-isopropyl-heptanoic acid;
(3S, 6S) -3-amino-6,8-dimethyl-nonanoic acid; and (3S, 6S) -3-amino-6,9-dimethyl-decanoic acid.

（式中、Ｒ₁、Ｒ₂およびＲ₃は上記の式Ｉに関するものと同様である）
の化合物、およびこのような化合物の製薬上許容可能な塩にも関する。 The present invention provides a compound of formula II:

Wherein R ₁ , R ₂ and R ₃ are the same as for formula I above.
And the pharmaceutically acceptable salts of such compounds.

  An example of a specific embodiment of the present invention is the following compound of formula I and pharmaceutically acceptable salts thereof: 2-aminomethyl-4-propyl-heptanoic acid.

（式中、Ｒ₃は、上記の式Ｉに関するものと同様である）
の化合物、およびこのような化合物の製薬上許容可能な塩にも関する。 The present invention provides a compound of formula IIA:

(Wherein R ₃ is the same as for formula I above)
And the pharmaceutically acceptable salts of such compounds.

Other particular embodiments of the invention include the following compounds of formula I and their pharmaceutically acceptable salts:
2-Aminomethyl-4-methyl-7-phenyl-heptanoic acid;
2-Aminomethyl-4-methyl-6-phenyl-hexanoic acid;
2-Aminomethyl-7- (4-fluoro-phenyl) -4-methyl-heptanoic acid;
2-Aminomethyl-7- (3-fluoro-phenyl) -4-methyl-heptanoic acid;
2-Aminomethyl-7- (2-fluoro-phenyl) -4-methyl-heptanoic acid;
2-Aminomethyl-7- (2,4-difluoro-phenyl) -4-methyl-heptanoic acid;
2-Aminomethyl-7- (3,4-difluoro-phenyl) -4-methyl-heptanoic acid;
2-Aminomethyl-4-methyl-7- (2-trifluoromethyl-phenyl) -heptanoic acid;
2-Aminomethyl-4-methyl-7- (3-trifluoromethyl-phenyl) -heptanoic acid;
2-Aminomethyl-4-methyl-7- (4-trifluoromethyl-phenyl) -heptanoic acid;

2-aminomethyl-4-methyl-6-phenylamino-hexanoic acid;
2-Aminomethyl-4-methyl-7-phenylamino-heptanoic acid;
2-Aminomethyl-4-methyl-8-phenylamino-octanoic acid;
(2R, 4R) -2-aminomethyl-4-methyl-7-phenyl-heptanoic acid;
(2R, 4R) -2-aminomethyl-4-methyl-6-phenyl-hexanoic acid;
(2R, 4R) -2-aminomethyl-7- (4-fluoro-phenyl) -4-methyl-heptanoic acid;
(2R, 4R) -2-aminomethyl-7- (3-fluoro-phenyl) -4-methyl-heptanoic acid;
(2R, 4R) -2-aminomethyl-7- (2-fluoro-phenyl) -4-methyl-heptanoic acid;
(2R, 4R) -2-aminomethyl-7- (2,4-difluoro-phenyl) -4-methyl-heptanoic acid;
(2R, 4R) -2-aminomethyl-7- (3,4-difluoro-phenyl) -4-methyl-heptanoic acid;

(2R, 4R) -2-aminomethyl-4-methyl-7- (2-trifluoromethyl-phenyl) -heptanoic acid;
(2R, 4R) -2-aminomethyl-4-methyl-7- (3-trifluoromethyl-phenyl) -heptanoic acid;
(2R, 4R) -2-aminomethyl-4-methyl-7- (4-trifluoromethyl-phenyl) -heptanoic acid;
(2R, 4R) -2-aminomethyl-4-methyl-6-phenylamino-hexanoic acid;
(2R, 4R) -2-aminomethyl-4-methyl-7-phenylamino-heptanoic acid;
(2R, 4R) -2-aminomethyl-4-methyl-8-phenylamino-octanoic acid;

(2R, 4S) -2-aminomethyl-4-methyl-7-phenyl-heptanoic acid;
(2R, 4S) -2-aminomethyl-4-methyl-6-phenyl-hexanoic acid;
(2R, 4S) -2-aminomethyl-7- (4-fluoro-phenyl) -4-methyl-heptanoic acid;
(2R, 4S) -2-aminomethyl-7- (3-fluoro-phenyl) -4-methyl-heptanoic acid;
(2R, 4S) -2-aminomethyl-7- (2-fluoro-phenyl) -4-methyl-heptanoic acid;
(2R, 4S) -2-aminomethyl-7- (2,4-difluoro-phenyl) -4-methyl-heptanoic acid;
(2R, 4S) -2-aminomethyl-7- (3,4-difluoro-phenyl) -4-methyl-heptanoic acid;

(2R, 4S) -2-aminomethyl-4-methyl-7- (2-trifluoromethyl-phenyl) -heptanoic acid;
(2R, 4S) -2-aminomethyl-4-methyl-7- (3-trifluoromethyl-phenyl) -heptanoic acid;
(2R, 4S) -2-aminomethyl-4-methyl-7- (4-trifluoromethyl-phenyl) -heptanoic acid;
(2R, 4S) -2-aminomethyl-4-methyl-6-phenylamino-hexanoic acid;
(2R, 4S) -2-aminomethyl-4-methyl-7-phenylamino-heptanoic acid;
(2R, 4S) -2-aminomethyl-4-methyl-8-phenylamino-octanoic acid;
(2R, 4S) -2-aminomethyl-6-cyclohexyl-4-ethyl-hexanoic acid;

2-Aminomethyl-3- (1-methyl-cyclopropyl) -propionic acid;
2-Aminomethyl-3- (1-ethyl-cyclopropyl) -propionic acid;
2-Aminomethyl-3- (1-propyl-cyclopropyl) -propionic acid;
2-Aminomethyl-3- (1-isopropyl-cyclopropyl) -propionic acid;
2-Aminomethyl-3- (1-butyl-cyclopropyl) -propionic acid;
2-Aminomethyl-3- (1-isobutyl-cyclopropyl) -propionic acid;
2-Aminomethyl-3- [1- (4-methyl-pentyl) -cyclopropyl] -propionic acid;

2-Aminomethyl-3- (1-methyl-cyclobutyl) -propionic acid;
2-Aminomethyl-3- (1-ethyl-cyclobutyl) -propionic acid;
2-Aminomethyl-3- (1-propyl-cyclobutyl) -propionic acid;
2-Aminomethyl-3- (1-methyl-cyclopentyl) -propionic acid;
2-Aminomethyl-3- (1-ethyl-cyclopentyl) -propionic acid;
2-Aminomethyl-3- (1-propyl-cyclopentyl) -propionic acid;
2-Aminomethyl-3- (1-methyl-cyclohexyl) -propionic acid;
2-Aminomethyl-3- (1-ethyl-cyclohexyl) -propionic acid;
2-Aminomethyl-3- (1-propyl-cyclohexyl) -propionic acid;
2-aminomethyl-4-ethyl-hexanoic acid;
2-Aminomethyl-4-ethyl-5-methyl-hexanoic acid;
2-aminomethyl-4-ethyl-heptanoic acid;
2-Aminomethyl-4-ethyl-6-methyl-heptanoic acid;
2-aminomethyl-4-ethyl-octanoic acid;
2-Aminomethyl-4-ethyl-7-methyl-octanoic acid;
2-aminomethyl-4-ethyl-nonanoic acid;

2-Aminomethyl-4-ethyl-8-methyl-nonanoic acid;
2-aminomethyl-4,4-dimethyl-heptanoic acid;
2-Aminomethyl-4,4,8-trimethyl-nonanoic acid;
2-aminomethyl-5-ethyl-heptanoic acid;
2-Aminomethyl-5-ethyl-6-methyl-heptanoic acid;
2-Aminomethyl-7-cyclopropyl-5-ethyl-heptanoic acid;
2-Aminomethyl-7-cyclobutyl-5-ethyl-heptanoic acid;
2-Aminomethyl-7-cyclopentyl-5-ethyl-heptanoic acid;
2-Aminomethyl-7-cyclohexyl-5-ethyl-heptanoic acid;
2-aminomethyl-5-ethyl-octanoic acid;
2-Aminomethyl-5-ethyl-7-methyl-octanoic acid;
2-aminomethyl-5-ethyl-nonanoic acid;

2-Aminomethyl-5-ethyl-8-methyl-nonanoic acid;
2-aminomethyl-4-cyclopropyl-butyric acid;
2-Aminomethyl-4- (1-methyl-cyclopropyl) -butyric acid;
2-Aminomethyl-4- (1-ethyl-cyclopropyl) -butyric acid;
2-aminomethyl-4-cyclobutyl-butyric acid;
2-Aminomethyl-4- (1-methyl-cyclobutyl) -butyric acid;
2-Aminomethyl-4- (1-ethyl-cyclobutyl) -butyric acid;
2-aminomethyl-4-cyclopentyl-butyric acid;
2-Aminomethyl-4- (1-methyl-cyclopentyl) -butyric acid;
2-Aminomethyl-4- (1-ethyl-cyclopentyl) -butyric acid;
2-aminomethyl-4-cyclohexyl-butyric acid;
2-Aminomethyl-4- (1-methyl-cyclohexyl) -butyric acid;
2-Aminomethyl-4- (1-ethyl-cyclohexyl) -butyric acid;

(2R, 4S) -2-aminomethyl-6-cyclopentyl-4-ethyl-hexanoic acid;
(2R, 4S) -2-aminomethyl-6-cyclobutyl-4-ethyl-hexanoic acid;
(2R, 4S) -2-Aminomethyl-6-cyclopropyl-4-ethyl-hexanoic acid.

Other specific embodiments of the invention include the following compounds of formula IIA and their pharmaceutically acceptable salts:
2-aminomethyl-4-methyl-hexanoic acid;
2-aminomethyl-4-methyl-heptanoic acid;
2-aminomethyl-4-methyl-octanoic acid;
2-aminomethyl-4-methyl-nonanoic acid;
2-aminomethyl-4-methyl-decanoic acid;

(2R, 4R) -2-aminomethyl-4-methyl-hexanoic acid;
(2R, 4R) -2-aminomethyl-4-methyl-heptanoic acid;
(2R, 4R) -2-aminomethyl-4-methyl-octanoic acid;
(2R, 4R) -2-aminomethyl-4-methyl-nonanoic acid;
(2R, 4R) -2-aminomethyl-4-methyl-decanoic acid;
(2R, 4S) -2-aminomethyl-4-methyl-hexanoic acid;
(2R, 4S) -2-aminomethyl-4-methyl-heptanoic acid;
(2R, 4S) -2-aminomethyl-4-methyl-octanoic acid;
(2R, 4S) -2-aminomethyl-4-methyl-nonanoic acid;
(2R, 4S) -2-aminomethyl-4-methyl-decanoic acid;

2-Aminomethyl-5-cyclopropyl-4-methyl-pentanoic acid;
2-Aminomethyl-5-cyclobutyl-4-methyl-pentanoic acid;
2-Aminomethyl-5-cyclopentyl-4-methyl-pentanoic acid;
2-Aminomethyl-5-cyclohexyl-4-methyl-pentanoic acid;
2-aminomethyl-6-cyclopropyl-4-methyl-hexanoic acid;
2-Aminomethyl-6-cyclobutyl-4-methyl-hexanoic acid;
2-Aminomethyl-6-cyclopentyl-4-methyl-hexanoic acid;
2-Aminomethyl-6-cyclohexyl-4-methyl-hexanoic acid;
2-Aminomethyl-7-cyclopropyl-4-methyl-heptanoic acid;
2-Aminomethyl-7-cyclobutyl-4-methyl-heptanoic acid;
2-Aminomethyl-7-cyclopentyl-4-methyl-heptanoic acid;
2-Aminomethyl-7-cyclohexyl-4-methyl-heptanoic acid;
2-Aminomethyl-8-cyclopropyl-4-methyl-octanoic acid;
2-Aminomethyl-8-cyclobutyl-4-methyl-octanoic acid;
2-Aminomethyl-8-cyclopentyl-4-methyl-octanoic acid;
2-Aminomethyl-8-cyclohexyl-4-methyl-octanoic acid;

(2R, 4S) -2-aminomethyl-5-cyclopropyl-4-methyl-pentanoic acid;
(2R, 4S) -2-aminomethyl-5-cyclobutyl-4-methyl-pentanoic acid;
(2R, 4S) -2-aminomethyl-5-cyclopentyl-4-methyl-pentanoic acid;
(2R, 4S) -2-aminomethyl-5-cyclohexyl-4-methyl-pentanoic acid;
(2R, 4S) -2-aminomethyl-6-cyclopropyl-4-methyl-hexanoic acid;
(2R, 4S) -2-aminomethyl-6-cyclobutyl-4-methyl-hexanoic acid;
(2R, 4S) -2-aminomethyl-6-cyclopentyl-4-methyl-hexanoic acid;
(2R, 4S) -2-aminomethyl-6-cyclohexyl-4-methyl-hexanoic acid;
(2R, 4S) -2-aminomethyl-7-cyclopropyl-4-methyl-heptanoic acid;
(2R, 4S) -2-aminomethyl-7-cyclobutyl-4-methyl-heptanoic acid;
(2R, 4S) -2-aminomethyl-7-cyclopentyl-4-methyl-heptanoic acid;
(2R, 4S) -2-aminomethyl-7-cyclohexyl-4-methyl-heptanoic acid;
(2R, 4S) -2-aminomethyl-8-cyclopropyl-4-methyl-octanoic acid;
(2R, 4S) -2-aminomethyl-8-cyclobutyl-4-methyl-octanoic acid;
(2R, 4S) -2-aminomethyl-8-cyclopentyl-4-methyl-octanoic acid;
(2R, 4S) -2-aminomethyl-8-cyclohexyl-4-methyl-octanoic acid;

(2R, 4R) -2-aminomethyl-5-cyclopropyl-4-methyl-pentanoic acid;
(2R, 4R) -2-aminomethyl-5-cyclobutyl-4-methyl-pentanoic acid;
(2R, 4R) -2-aminomethyl-5-cyclopentyl-4-methyl-pentanoic acid;
(2R, 4R) -2-aminomethyl-5-cyclohexyl-4-methyl-pentanoic acid;
(2R, 4R) -2-aminomethyl-6-cyclopropyl-4-methyl-hexanoic acid;
(2R, 4R) -2-aminomethyl-6-cyclobutyl-4-methyl-hexanoic acid;
(2R, 4R) -2-aminomethyl-6-cyclopentyl-4-methyl-hexanoic acid;
(2R, 4R) -2-aminomethyl-6-cyclohexyl-4-methyl-hexanoic acid;
(2R, 4R) -2-aminomethyl-7-cyclopropyl-4-methyl-heptanoic acid;
(2R, 4R) -2-aminomethyl-7-cyclobutyl-4-methyl-heptanoic acid;
(2R, 4R) -2-aminomethyl-7-cyclopentyl-4-methyl-heptanoic acid;
(2R, 4R) -2-aminomethyl-7-cyclohexyl-4-methyl-heptanoic acid;
(2R, 4R) -2-aminomethyl-8-cyclopropyl-4-methyl-octanoic acid;
(2R, 4R) -2-aminomethyl-8-cyclobutyl-4-methyl-octanoic acid;
(2R, 4R) -2-aminomethyl-8-cyclopentyl-4-methyl-octanoic acid; and (2R, 4R) -2-aminomethyl-8-cyclohexyl-4-methyl-octanoic acid.

（式中、Ｒは上記の式Ｉに関するものと同様である）
の化合物およびそれらの製薬上許容可能な塩にも関する。 The present invention provides a compound of formula III:

(Wherein R is the same as for formula I above)
And the pharmaceutically acceptable salts thereof.

（式中、Ｒ₁およびＲ₃は上記の式Ｉの化合物と同様に定義される）
の化合物およびそれらの製薬上許容可能な塩にも関する。 The present invention relates to Formula IV:

(Wherein R ₁ and R ₃ are defined similarly to the compounds of formula I above)
And the pharmaceutically acceptable salts thereof.

Other specific embodiments of the present invention include the following compounds of formula IV and their pharmaceutically acceptable salts:
2-Aminomethyl-6-cyclopropyl-5-methyl-hexanoic acid;
2-Aminomethyl-6-cyclobutyl-5-methyl-hexanoic acid;
2-Aminomethyl-6-cyclopentyl-5-methyl-hexanoic acid;
2-Aminomethyl-6-cyclohexyl-5-methyl-hexanoic acid;
2-Aminomethyl-7-cyclopropyl-5-methyl-heptanoic acid;
2-Aminomethyl-7-cyclobutyl-5-methyl-heptanoic acid;
2-Aminomethyl-7-cyclopentyl-5-methyl-heptanoic acid;
2-Aminomethyl-7-cyclohexyl-5-methyl-heptanoic acid;
2-Aminomethyl-8-cyclopropyl-5-methyl-octanoic acid;
2-Aminomethyl-8-cyclobutyl-5-methyl-octanoic acid;
2-Aminomethyl-8-cyclopentyl-5-methyl-octanoic acid;
2-Aminomethyl-8-cyclohexyl-5-methyl-octanoic acid;

2-aminomethyl-5-methyl-heptanoic acid;
2-aminomethyl-5-methyl-octanoic acid;
2-aminomethyl-5-methyl-heptanoic acid;
2-aminomethyl-5-methyl-nonanoic acid;

(2R, 6S) -2-aminomethyl-6-cyclopropyl-5-methyl-hexanoic acid;
(2R, 6S) -2-aminomethyl-6-cyclobutyl-5-methyl-hexanoic acid;
(2R, 6S) -2-aminomethyl-6-cyclopentyl-5-methyl-hexanoic acid;
(2R, 6S) -2-aminomethyl-6-cyclohexyl-5-methyl-hexanoic acid;
(2R, 6S) -2-aminomethyl-7-cyclopropyl-5-methyl-heptanoic acid;
(2R, 6S) -2-aminomethyl-7-cyclobutyl-5-methyl-heptanoic acid;
(2R, 6S) -2-aminomethyl-7-cyclopentyl-5-methyl-heptanoic acid;
(2R, 6S) -2-aminomethyl-7-cyclohexyl-5-methyl-heptanoic acid;
(2R, 6S) -2-aminomethyl-8-cyclopropyl-5-methyl-octanoic acid;
(2R, 6S) -2-aminomethyl-8-cyclobutyl-5-methyl-octanoic acid;
(2R, 6S) -2-aminomethyl-8-cyclopentyl-5-methyl-octanoic acid;
(2R, 6S) -2-aminomethyl-8-cyclohexyl-5-methyl-octanoic acid;
(2R, 6S) -2-aminomethyl-5-methyl-heptanoic acid;
(2R, 6S) -2-aminomethyl-5-methyl-octanoic acid;
(2R, 6S) -2-aminomethyl-5-methyl-heptanoic acid;
(2R, 6S) -2-aminomethyl-5-methyl-nonanoic acid;

(2R, 6R) -2-aminomethyl-6-cyclopropyl-5-methyl-hexanoic acid;
(2R, 6R) -2-aminomethyl-6-cyclobutyl-5-methyl-hexanoic acid;
(2R, 6R) -2-aminomethyl-6-cyclopentyl-5-methyl-hexanoic acid;
(2R, 6R) -2-aminomethyl-6-cyclohexyl-5-methyl-hexanoic acid;
(2R, 6R) -2-aminomethyl-7-cyclopropyl-5-methyl-heptanoic acid;
(2R, 6R) -2-aminomethyl-7-cyclobutyl-5-methyl-heptanoic acid;
(2R, 6R) -2-aminomethyl-7-cyclopentyl-5-methyl-heptanoic acid;
(2R, 6R) -2-aminomethyl-7-cyclohexyl-5-methyl-heptanoic acid;
(2R, 6R) -2-aminomethyl-8-cyclopropyl-5-methyl-octanoic acid;
(2R, 6R) -2-aminomethyl-8-cyclobutyl-5-methyl-octanoic acid;
(2R, 6R) -2-aminomethyl-8-cyclopentyl-5-methyl-octanoic acid;
(2R, 6R) -2-aminomethyl-8-cyclohexyl-5-methyl-octanoic acid;
(2R, 6R) -2-aminomethyl-5-methyl-heptanoic acid;
(2R, 6R) -2-aminomethyl-5-methyl-octanoic acid;
(2R, 6R) -2-aminomethyl-5-methyl-heptanoic acid; and (2R, 6R) -2-aminomethyl-5-methyl-nonanoic acid.

  The present invention provides a therapeutically effective amount of a compound of formula I, IA, IA-1, IA-2, IB, IC, II, IIA, III or IV, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable It also relates to a pharmaceutical composition comprising a suitable carrier.

  The present invention relates to epilepsy, syncope, fibromyalgia, hypoxia, cranial disorders, hot flashes, essential tremors, chemical dependence and addiction in mammals such as humans (eg alcohol, amphetamine (or amphetamine-like substances) ), Caffeine, cannabis, cocaine, heroin, hallucinogens, tobacco, inhalants and aerosol propellants, nicotine, opioids, phenylglycine derivatives, sedatives, hypnotics, benzodiazepines and other anti-anxiety agents ), As well as such addiction or addiction, fertility behavior, eg, withdrawal syndrome associated with gambling; migraine, spasticity, eg, muscle spasticity, and hypotonia with paralysis, arthritis, irritable bowel syndrome (IBS) Chronic pain, acute pain, neuropathic pain, vascular headache, sinus headache, inflammatory disorders (eg Rheumatoid arthritis, osteoarthritis, disease modification of osteoarthritis disease, cartilage damage, psoriasis), polyuria, premenstrual syndrome, premenstrual discomfort disorder, tinnitus and stomach damage A mammal in need of such treatment with a therapeutically effective amount of a compound of formula I, IA, IA-1, IA-2, IB, IC, II, IIA, III or IV, or a pharmaceutically acceptable salt thereof It also relates to a method comprising administering possible salts.

The present invention is a method for promoting weight gain in mammals, such as smoking cessation, withdrawal from addictive substances and dependence, loss of appetite, cancer, mosquitoes with age and / or volition, or monkey mammals. A mammal in need of such treatment with a therapeutically effective amount of a compound of formula I, IA, IA-1, IA-2, IB, IC, II, IIA, III or IV, or a pharmaceutically acceptable salt thereof It also relates to a method comprising administering an acceptable salt.
The present invention also covers treating a neurodegenerative disorder called acute brain injury. Examples of these include, but are not limited to, stroke, head trauma and suffocation.

  Stroke refers to a cerebral vascular disease and can also be referred to as a cerebral vascular accident (CVA), and examples include acute thromboembolic stroke. Stroke includes both focal and general ischemia. Furthermore, transient cerebral ischemic attacks and other cerebral vascular problems associated with cerebral ischemia, such as carotid endarterectomy or other cerebrovascular or vascular surgical procedures, or diagnostic hemangiomas such as cerebral Also included are those that occur in patients undergoing angiography and the like.

  Compounds of formula I, IA, IA-1, IA-2, IB, IC, II, IIA, III or IV may be used for head trauma, spinal cord trauma or systemic anoxia, hypoxia, hypoglycemia, low It is also useful for the treatment of blood pressure damage and similar damage seen during procedures from dislocation reduction, hyperfusion and hypoxia. They are also useful in preventing neuronal damage that occurs in cardiac arrest and intussusception during perinatal asphyxia during accidental events of intracranial hemorrhage during cardiac bypass surgery.

  The present invention relates to delirium, dementia, and amnestic and other cognitive or neurodegenerative disorders such as Parkinson's disease (PD), Huntington's disease (HD), Alzheimer's disease, senile dementia, Alzheimer type in mammals such as humans Dementia, memory impairment, vascular dementia, and other dementias for HIV disease, head trauma, Parkinson's disease, Huntington's disease, Pick's disease, Creutzfeldt-Jakob disease, or for many etiologies; movement disorders such as Immobility, dyskinesia, spasticity, Tourette syndrome, Scott syndrome, PALSYS and ataxia syndrome; extrapyramidal movement disorders such as drug-induced movement disorders such as neuroleptic drug-induced acute dystonia, neuroleptic Drug-induced acute restlessness, neuroleptic-induced delayed dyskinesia and drug-induced postural tremor Down's syndrome; demyelinating diseases such as multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS), peripheral neuropathies such as diabetic and chemotherapy-induced neuropathy, and postherpetic neuralgia, trigeminal Treatment of disorders or symptoms selected from the group consisting of neuralgia, segmental or intercostal neuralgia and other neuralgia; and cerebral vascular disorders for acute or chronic cerebrovascular injury, eg cerebral infarction, subarachnoid hemorrhage or cerebral edema A method comprising an amount of a compound of formula I, IA, IA-1, IA-2, IB, IC, II, IIA, III or IV, or a pharmaceutical thereof effective to treat such a disorder or condition It also relates to a method comprising administering a top acceptable salt to the mammal.

  Cognition is a therapeutically effective amount of a compound of formula I, IA, IA-1, IA-2, IB, IC, II, IIA, III or IV in a patient with fibromyalgia, Alzheimer's disease and Parkinson's disease, or By administering the pharmaceutically acceptable salt to a mammal in need of such treatment, it can also be enhanced by enhancing sleep in the affected mammal, eg, a human.

  Pain refers to acute as well as chronic pain. Acute pain is usually short in duration and is associated with an active form of the sympathetic nervous system. Examples are postoperative pain and allodynia. Chronic pain is defined as pain that usually lasts 3-6 months, examples include somatic and psychogenic pain. Other pain is nociceptive.

  Examples of types of pain that can be treated with the compounds of formula I, IA, IA-1, IA-2, IB, IC, II, IIA, III and IV of the present invention and pharmaceutically acceptable salts thereof include: Tissue and peripheral honorary names such as pain due to acute trauma, pain associated with osteoarthritis and rheumatoid arthritis, musculoskeletal pain such as pain experienced after trauma; spinal pain, toothache, myofascial pain syndrome, Painiotomy pain and pain due to burn; deep and visceral pain such as heart pain, muscle pain, eye pain, orofacial pain such as tooth pain, abdominal pain, gynecological pain such as dysmenorrhea, labor pain Pain associated with endometriosis; pain associated with nerve and root injury, eg peripheral neuropathy, eg nerve entrapment and brachial plexus ablation, amputation, peripheral neuropathy, pain Tic, atypical facial neuralgia, nerve root injury, trigeminal neuralgia, neuropathic back pain, HIV-related neuropathic pain, cancer-related neuropathic pain, diabetic neuropathic pain and arachnoiditis; often referred to as cancer pain Related neuropathic and non-neuropathic pain; central nervous system pain, eg pain due to spinal cord or brainstem injury; low back pain; sciatica; phantom limb pain, headache, eg migraine and other vascular headache, acute or Chronic tension headache, cluster headache, temporal and maxillary sinus pain; pain due to ankylosing spondylitis and ventilation; pain caused by increased bladder contraction; postoperative pain; scar pain; and chronic non-neuropathic Pain, eg, fibromyalgia, pain associated with HIV, rheumatism and osteoarthritis, arthralgia and myalgia, sprains, contusions and trauma, eg fractures; and surgery Pain, and the like.

  Still other pains are caused by peripheral sensory nerve damage or infection. Examples include, but are not limited to, peripheral nerve trauma, herpes virus infection, diabetes mellitus, fibromyalgia, burning pain, plexus detachment, neuroma, limb amputation and vasculitis. Neuropathic pain can also be caused by nerve damage from chronic alcoholism, human immunodeficiency virus infection, hypothyroidism, uremia or vitamin deficiency. Neuropathic pain includes, but is not limited to, pain caused by nerve damage, such as pain experienced by diabetic patients.

Psychogenic pain occurs without organ origin such as back pain, atypical facial pain and chronic headache.
Other types of pain include: inflammatory pain, osteoarthritic pain, trigeminal neuralgia, cancer pain, diabetic neuropathy, non-rest leg syndrome, acute herpes and postherpetic neuralgia, burning pain, brachial plexus ablation Occipital neuralgia, ventilation, phantom limb pain, burns and other forms of neuralgia, neuropathy and idiopathic pain syndrome.

  The compounds of the present invention are also useful in the treatment of depression. Depression can be the result of stress related to personality loss or the result of idiopathic origin organ disease. There is a strong tendency towards familial development of some forms of depression, suggesting a mechanistic cause for at least some forms of depression. Diagnosis of depression is made primarily by quantifying changes in the patient's mood. These mood assessments are generally performed by a physician or quantified by a neuropsychologist using a confirmatory rating scale, such as the Hamilton Depression Rating Scale or a simple psychiatric rating scale. A number of other measures have been developed to quantify and measure the extent of mood changes in patients with depression, such as insomnia, difficulty concentrating, lack of energy, valuelessness and guilt. The criteria for the diagnosis of depression and all psychiatric diagnoses are collected in the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition), published by the American Psychiatric Association (1994), called the DSM-IV-R Manual. ing.

  The present invention relates to mood disorders such as depression, or particularly depression disorders such as single incidental or recurrent major depression disorders, thymic dysfunction disorders, depressive neurosis and neurotic depression in mammals such as humans Stupor depression, eg anorexia, weight loss, insomnia, premature waking and psychomotor retardation, atypical depression (or reactive depression), eg increased appetite, excessive sleep, psychomotor agitation or hypersensitivity, seasonality Affective disorder and childhood depression; or bipolar disorder or manic depression, such as bipolar I disorder, bipolar II disorder and circulatory temperament disorder; behavioral disorder and division behavior disorder; anxiety disorder such as panic disorder (square phobia) With or without), agoraphobia (no history of panic disorder), certain phobias, such as certain animal phobias, flight fears, social anxiety disorders, social fears , Obsessive-compulsive disorder, stress disorder such as post-traumatic stress disorder and acute stress disorder, and generalized anxiety disorder; borderline personality disorder; schizophrenia and other psychotic disorders such as schizophrenic type disorder, schizoaffective disorder, Delusional disorder, short-term psychotic disorder, shared psychotic disorder, psychotic disorder with delusions or hallucinations, psychotic episodes of anxiety, anxiety related to psychosis, psychotic mood disorders, eg severe major depressive disorder; psychotic Mood disorder associated with disability, eg, acute manic depression associated with bipolar disorder, mood disorder associated with schizophrenia; behavioral disturbance associated with mental retardation, autistic disorder, and behavioral disorder A method of treating a disorder or symptom, wherein the amount of Formula I, IA, IA-1, IA-2, I is effective to treat such disorder or symptom Relates IC, II, IIA, also a compound of III or IV, or a pharmaceutically acceptable salt thereof in a method comprising administering to said mammals.

  The compounds of the present invention are also useful for the treatment of sleep disorders. Sleep disorders are disturbances that affect sleep ability and / or sleep ability, are involved in excessive sleep, or cause abnormal behavior related to sleep. Such disorders include, for example, insomnia, drug-related insomnia, excessive sleep, sleep seizures, sleep apnea syndrome, and sleep abnormal behavior.

  The present invention relates to sleep disorders (eg, insomnia, drug-related insomnia, REM sleep disorders, excessive sleep, sleep seizures, sleep-wake cycle disorders, sleep apnea syndrome, sleep abnormal behavior, non-rest in mammals such as humans. A method of treating a disorder or symptom selected from the group consisting of: leg syndrome, jet lag, periodic limb movement disorders and sleep building alterations, and sleep disorders associated with shift work and irregular work hours, An amount of a compound of formula I, IA, IA-1, IA-2, IB, IC, II, IIA, III or IV, or a pharmaceutically acceptable salt thereof, effective to treat such disorders or symptoms Also comprising administering to a mammal as described above.

  Compounds of formula I, IA, IA-1, IA-2, IB, IC, II, IIA, III and IV contain at least one chiral center and can therefore exist in different enantiomeric and diastereomeric forms. The present invention relates to formulas I, IA, IA-1, IA-2, IB, IC, II, both as racemic mixtures of such compounds, and as individual enantiomers and diastereoisomers, and mixtures thereof. , IIA, III and IV all optical isomers, and all stereoisomers, and all pharmaceutical compositions and methods of treatment described above containing or using them, respectively. Individual isomers can be produced by known methods, for example by optical resolution, optical selection reactions or chromatographic separations in the preparation of the final product or its intermediates. Individual enantiomers of the compounds of the invention may have advantages compared to racemic mixtures of these compounds in the treatment of various disorders or conditions.

The present invention also includes isotopically labeled compounds that are identical to those listed in Formulas I, IA, IA-1, IA-2, IB, IC, II, IIA, III and IV, but in fact, One or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number normally found in reality. Examples of isotopes that can be incorporated into the compounds of the present invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine isotopes such as ² H, ³ H, ¹³ C, ¹¹ C, ¹⁴ C, respectively. include ^{15 N, 18 O, 17 O} , 31 P, 32 P, 35 S, 18 F and ³⁶ Cl. Compounds of the present invention, prodrugs thereof, and pharmaceutically acceptable salts of the above compounds or of the above prodrugs that contain the aforementioned isotopes and / or other isotopes of other atoms are within the scope of the present invention. It is. Certain isotopically-labelled compounds of the present invention, for example those into which radioactive isotopes such as ³ H and ¹⁴ C are incorporated, are useful in drug and / or substrate tissue distribution assays. Tritiated, ie ³ H, and carbon-14, ie ¹⁴ C, isotopes are particularly preferred for their ease of preparation and detectability. In addition, substitution with heavier isotopes, such as deuterium, i.e. ² H, provides certain therapeutic benefits resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements, and therefore Can be selected in any environment. The isotope-labeled compounds of formula I and their prodrugs of the present invention are generally shown in the schemes and / or in the examples below by substituting readily available isotope-labeled reagents instead of non-isotopically labeled reagents And can be prepared by performing the procedures disclosed in the preparations.

  The term “alkyl”, as used herein, unless otherwise stated, includes saturated monovalent hydrocarbons having straight, branched or cyclic moieties or combinations thereof. Examples of “alkyl” groups include methyl, ethyl, propyl, isopropyl, butyl, iso-, sec- and tert-butyl, pentyl, hexyl, heptyl, 3-ethylbutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl , Norbornyl and the like, but are not limited thereto.

  The term “alkoxy” as used herein means “alkyl-O—” unless otherwise indicated, where “alkyl” is as defined above. Examples of “alkoxy” groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy and pentoxy.

  The term “treating”, as used herein, prevents, reverses, reduces, or inhibits the progression of a disorder or symptom to which such term applies. Or preventing one or more symptoms of such symptoms or disorders. The term “treatment”, as used herein, refers to the act of treating, as “treating” is defined immediately above.

  Since amino acids are amphoteric, pharmacologically compatible salts are suitable inorganic or organic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, oxalic acid, lactic acid, citric acid, malic acid, salicylic acid, malonic acid, Maleic acid, succinic acid and ascorbic acid salts. Starting from the corresponding hydroxides or carbonates, alkali or alkaline earth metals such as sodium, potassium, magnesium or calcium are produced. Salts with quaternary ammonium ions can also be prepared using, for example, tetramethyl-ammonium ions.

  The effectiveness of orally administered drugs depends on the efficient delivery of the drug across the mucosal epithelium and its stability in the intestinal-liver circulation. Agents that are effective after parenteral administration but that are orally less effective or whose plasma half-life is considered too short may be chemically modified into prodrug forms.

  A prodrug may be chemically modified and biologically inert at its site of action, but is degraded to the parent bioactive form by one or more enzymatic or other in vivo processes. Or a drug that can be modified.

This chemically modified drug or prodrug has a different pharmacokinetic profile than the parent drug, making it easier to absorb across the mucosal epithelium, better salt formation and / or solubility, and improved systemic stability ( For example to increase plasma half-life). These chemical modifications are shown below:
1) Ester or amide derivatives that can be cleaved, for example by esterases or lipases. With respect to ester derivatives, the ester is derived from the carboxylic acid moiety of the drug molecule by known means. With respect to amide derivatives, the amide can be derived from the carboxylic acid moiety or amine moiety of the drug molecule by known means.
2) Peptides that can be recognized by specific or non-specific proteinases. The peptide can be attached to the drug molecule via amide bond formation with the amine or carboxylic acid moiety of the drug molecule by known methods.
3) Derivatives that accumulate at the site of action by membrane selection in prodrug form or modified prodrug form.
4) Any combination of 1-3.

Recent studies in animal studies show that oral absorption of certain drugs can be increased by the preparation of “soft” quaternary salts. Unlike regular quaternary salts, such as RN ⁺ (CH ₃ ) ₃ , quaternary salts are referred to as “soft” quaternary salts because they can release the active agent upon hydrolysis.

  “Soft” quaternary salts have useful physical properties compared to the base drug or salts thereof. Water solubility can be increased compared to other salts, such as hydrochloride, but more importantly, increased absorption of the drug from the small intestine can be observed. Increased absorption is likely that the “soft” quaternary salt has surfactant properties and can form micelles and non-ionized ion pairs with bile acids etc. (which can penetrate the small intestinal epithelium more efficiently) Because of the fact that. Prodrugs are rapidly hydrolyzed after absorption to release the active parent drug.

Prodrugs of compounds of formulas I, IA, IA-1, IA-2, IB, IC, II, IIA, III and IV are included within the scope of the invention. Prodrugs and soft drugs are known in the art (Palomino E., Drugs of the Future, 1990; 15 (4): 361-368). The last two references are incorporated herein by reference.
Some of the compounds of the present invention may exist in unsolvated forms as well as solvated forms, eg, hydrated forms. In general, the solvated forms, eg, hydrated forms, are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention.

Detailed Description of the Invention The compounds of the present invention may be prepared as follows. In the following reaction schemes and discussion, structural formulas I, IA, IA-1, IA-2, IB, IC, II, IIA, III and IV and the radicals R ₁ , R ₂ , R ₃ , R ₄ , R ₅ And R ₆ are the same as above unless otherwise specified.

There are a variety of methods for the preparation of chiral and racemic β-amino acids. Such a method can be found in “Enantioselective Synthesis of β-Amino Acids”, Juaristi, Eusebio; Editor. USA, 1997, Wiley-VCH, New York, NY.
The following methods are illustrative of methods that can be utilized for the preparation of such compounds and are not limiting in scope.

Lazar, et al, Synth. Commun, 1998, 28(2), 219-224の手法に従って、式ＩＡの化合物は、マロン酸および酢酸アンモニウムの存在下で、アルコール溶媒、例えばエタノール中の式１の化合物を加熱、還流することにより調製され得る。式１のアルデヒドは、当業者に周知の方法を用いて、市販物質から調製され得る。 Method A

According to the procedure of Lazar, et al, Synth. Commun, 1998, 28 (2), 219-224, the compound of formula IA is a compound of formula 1 in an alcohol solvent, for example ethanol, in the presence of malonic acid and ammonium acetate. Can be prepared by heating to reflux. The aldehydes of formula 1 can be prepared from commercially available materials using methods well known to those skilled in the art.

Compounds that can be produced by the above methods include, but are not limited to:
3-amino-6-cyclopropyl-5-methyl-hexanoic acid;
3-amino-6-cyclobutyl-5-methyl-hexanoic acid;
3-amino-6-cyclopentyl-5-methyl-hexanoic acid;
3-amino-6-cyclohexyl-5-methyl-hexanoic acid;
3-amino-7-cyclopropyl-5-methyl-heptanoic acid;
3-amino-7-cyclobutyl-5-methyl-heptanoic acid;
3-Amino-7-cyclopentyl-5-methyl-heptanoic acid;
3-Amino-7-cyclohexyl-5-methyl-heptanoic acid;
3-amino-8-cyclopropyl-5-methyl-octanoic acid;
3-amino-8-cyclobutyl-5-methyl-octanoic acid;
3-amino-8-cyclopentyl-5-methyl-octanoic acid;
3-Amino-8-cyclohexyl-5-methyl-octanoic acid;
3-amino-6-cyclopropyl-5,5-dimethyl-hexanoic acid;
3-amino-6-cyclobutyl-5,5-dimethyl-hexanoic acid;
3-amino-6-cyclopentyl-5,5-dimethyl-hexanoic acid;
3-amino-6-cyclohexyl-5,5-dimethyl-hexanoic acid;
3-amino-7-cyclopropyl-5,5-dimethyl-heptanoic acid;
3-amino-7-cyclobutyl-5,5-dimethyl-heptanoic acid;
3-Amino-7-cyclopentyl-5,5-dimethyl-heptanoic acid;
3-Amino-7-cyclohexyl-5,5-dimethyl-heptanoic acid.

  As illustrated in Method B above, the use of chiral amine addition to α, β-unsaturated systems as a synthetic approach to β amino acids has been described previously (eg, SG Davies et al, J. Chem. Soc Chem. Commun, 1153, 1993; SG Davies, Synlett, 1994, 117; Ishikawa et al, Synlett, 1998, 1291; Hawkins, J. Org. Chem., 1985, 51, 2820). Referring to Method B above, compounds of formula IA can be prepared from the corresponding compounds of formula 7 using conditions well known to those skilled in the art wherein PG can be removed by hydrolysis or hydrogenolysis. (Represents a suitable ester protecting group) (See TW Greene and PGM Wuts., “Protective groups in organic synthesis”, Wiley, 1991 for a detailed description of the generation and removal of suitable protecting groups). For example, the reaction may be at a temperature from about room temperature to about the reflux temperature of the reaction mixture, preferably at the reflux temperature, by treatment with a suitable acid, such as hydrochloric acid or sulfuric acid, or at a temperature from about room temperature to about the reflux temperature. It can be carried out under hydrolysis conditions, preferably at about room temperature, by treatment with a suitable inorganic base such as sodium hydroxide, potassium hydroxide or lithium hydroxide, preferably sodium hydroxide. This reaction is preferably carried out with hydrochloric acid at reflux temperature. However, when PG is t-butyl, the reaction is preferably carried out in trifluoroacetic acid (TFA). When PG is a basic group, the hydrolysis can be carried out under basic conditions using methods well known to those skilled in the art, for example using sodium or potassium hydroxide.

  Compounds of formula 7 can be prepared from the corresponding compounds of formula 6 using hydrocracking conditions well known to those skilled in the art. For example, this reaction may be carried out under a hydrogen atmosphere (about 1-5 atmospheric pressure) using, for example, a palladium metal catalyst, such as palladium hydroxide on carbon, or palladium on carbon, in a solvent such as methanol, ethanol or tetrahydrofuran, or It can be carried out by treating the compound of formula 6 with Raney nickel to produce the desired compound of formula 7. Preferably the reaction is carried out using palladium on carbon in ethanol at about 1 atmosphere of hydrogen.

  The compound of formula 6 is prepared at a temperature of about −80 ° C. to about 25 ° C. with a suitable base such as lithium diisopropylamine, n-butyllithium, or lithium in a solvent such as ethyl ether or preferably tetrahydrofuran (THF). Or after treatment with potassium bis (trimethylsilyl) amide, a suitable amine such as (R)-(+)-N-benzyl-α-methylbenzylamine, (S)-(−)-N-benzyl-α-methyl It can be prepared by treating the corresponding compound of formula 4 with benzylamine and then adding the appropriate compound of formula 4. The stereochemistry of the amine for nitrogen establishes the stereochemistry for the final product nitrogen. Preferably this reaction is according to the method described by Bull, Steven D .; Davies, Stephen G .; and Smith, Andrew D., J. Chem. Soc., Perkin Trans. 1, 2001, 22, 2931-2938. After deprotonation with n-butyl-lithium in tetrahydrofuran at a temperature of about -78 ° C, (R)-(+)-N-benzyl-α-methylbenzylamine, (S)-(-)- Performed with N-benzyl-α-methylbenzylamine. Preferably this reaction is according to the method described by Bull, Steven D .; Davies, Stephen G .; and Smith, Andrew D., J. Chem. Soc., Perkin Trans. 1, 2001, 22, 2931-2938. After deprotonation with n-butyl-lithium in tetrahydrofuran at a temperature of about −78 ° C., (R)-(+)-N-benzyl-α-methylbenzylamine or (S)-(−) — Performed with N-benzyl-α-methylbenzylamine.

  The compound of formula 4 is used with a suitable phosphate ester in the presence of a suitable base such as sodium hydride, lithium diisopropylamide or triethylamine and lithium chloride or lithium bromide in a solvent such as ether or THF. By treating them, they can be prepared from the corresponding compounds of formula 3. Preferably the compound of formula 3 is reacted with a phosphate ester (ALK = methyl, ethyl, isopropyl, benzyl, etc.) in the presence of lithium bromide and triethylamine in tetrahydrofuran at about room temperature. Compounds of formula 3 can be prepared from commercially available materials using methods well known to those skilled in the art. It is understood that the compound of formula 3 may possess one or more stereocenters. Using the methods described above, compounds having specific stereochemical configurations can be prepared.

Compounds that can be produced by this method include, but are not limited to:
(3S, 5R) -3-Amino-6-cyclopropyl-5-methyl-hexanoic acid;
(3S, 5R) -3-Amino-6-cyclobutyl-5-methyl-hexanoic acid;
(3S, 5R) -3-Amino-6-cyclopentyl-5-methyl-hexanoic acid;
(3S, 5R) -3-Amino-6-cyclohexyl-5-methyl-hexanoic acid;
(3S, 5R) -3-Amino-8-cyclopropyl-5-methyl-octanoic acid;
(3S, 5R) -3-Amino-8-cyclobutyl-5-methyl-octanoic acid;
(3S, 5R) -3-Amino-8-cyclopentyl-5-methyl-octanoic acid;
(3S, 5R) -3-Amino-8-cyclohexyl-5-methyl-octanoic acid;
(3S, 5S) -3-Amino-6-cyclopropyl-5-methyl-hexanoic acid;
(3S, 5S) -3-Amino-6-cyclobutyl-5-methyl-hexanoic acid;
(3S, 5S) -3-Amino-6-cyclopentyl-5-methyl-hexanoic acid;
(3S, 5S) -3-Amino-6-cyclohexyl-5-methyl-hexanoic acid;

(3S, 5S) -3-Amino-8-cyclopropyl-5-methyl-octanoic acid;
(3S, 5S) -3-Amino-8-cyclobutyl-5-methyl-octanoic acid;
(3S, 5S) -3-Amino-8-cyclopentyl-5-methyl-octanoic acid;
(3S, 5S) -3-Amino-8-cyclohexyl-5-methyl-octanoic acid;
(3S) -3-amino-6-cyclopropyl-5,5-dimethyl-hexanoic acid;
(3S) -3-amino-6-cyclobutyl-5-dimethyl-hexanoic acid;
(3S) -3-amino-6-cyclopentyl-5,5-dimethyl-hexanoic acid;
(3S) -3-amino-6-cyclohexyl-5,5-dimethyl-hexanoic acid;
(3S) -3-Amino-7-cyclopropyl-5,5-dimethyl-heptanoic acid;
(3S) -3-Amino-7-cyclobutyl-5,5-dimethyl-heptanoic acid;
(3S) -3-Amino-7-cyclopentyl-5,5-dimethyl-heptanoic acid;
(3S) -3-Amino-7-cyclohexyl-5,5-dimethyl-heptanoic acid.

  Diastereoalkylation of imides such as those of Formula 10 to obtain chiral succinate analogs, such as that of Formula 11, has been previously described as one approach for preparing β-amino acids (eg, Evans et al. al, J. Org. Chem., 1999, 64, 6411; Sibi and Deshpande, J. Chem. Soc. Perkin Trans. 1., 2000, 1461; Arvanitis et al, J. Chem. Soc. Perki Trans 1., 1998, 521).

  The compound of structural formula 11 is a suitably derived ester with an organometallic base in a solvent such as tetrahydrofuran, ether, etc., for example lithium diisopropylamide, or lithium bis (trimethylsilyl) amide or sodium bis (trimethylsilyl) amide. (PG as described above, LG = Br or I or Cl), such as t-butyl bromoacetate, benzyl bromoacetate in the presence of a compound of structural formula 10 can be prepared. The reaction is carried out using sodium bis (trimethylsilyl) amide in tetrahydrofuran at minus 78 ° C. and treating the resulting anionic intermediate with t-butyl bromoacetate at −78 ° C. to −30 ° C. Can be executed.

  A compound of formula 12 is prepared by hydrolyzing the corresponding compound of formula 11 in the presence of lithium hydroxide and hydrogen peroxide in a solvent such as water or THF at a temperature of about 0 ° C. to about room temperature. Can be done. Preferably this reaction is carried out according to the methods described in the literature (see Yuen-PW., Kanter GD, Taylor CP, and Vartanian MG, Bioorganic and Medicinal Chem. Lett., 1994; 4 (6): 823-826). It can be carried out at about 0 ° C. with hydrogen peroxide and lithium hydroxide in aqueous tetrahydrofuran.

In the presence of a suitable alcohol such as t-butanol, benzyl alcohol or p-methoxybenzyl alcohol in a suitable solvent such as toluene, benzene or THF at a temperature from about 50 ° C. to about the reflux temperature of the reaction congo. Treatment of the compound of formula 12 with diphenylphosphoryl azide, yielding the corresponding compound of formula 13 wherein R ₅ is methyl, ethyl, t-butyl, benzyl or p-methoxybenzyl. R ₅ depends on the choice of alcohol used. Preferably, this reaction is carried out with toluene solvent in the presence of p-methoxybenzyl alcohol under reflux conditions.

  Compounds of formula 13 can be converted to the desired compounds of formula IA by hydrolysis or hydrogenolysis using conditions well known to those skilled in the art (for a detailed description of the generation and removal of suitable protecting groups, see TW Greene and PGM Wuts., “Protective groups in organic synthesis”, Wiley, 1991). For example, the reaction may be at a temperature from about room temperature to about the reflux temperature of the reaction mixture, preferably at the reflux temperature, by treatment with a suitable acid, such as hydrochloric acid or sulfuric acid, or at a temperature from about room temperature to about the reflux temperature. It can be carried out under hydrolysis conditions, preferably at about room temperature, by treatment with a suitable inorganic base such as sodium hydroxide, potassium hydroxide or lithium hydroxide, preferably sodium hydroxide. This reaction is preferably carried out with hydrochloric acid at reflux temperature. However, when PG is t-butyl, the reaction is preferably carried out in trifluoroacetic acid (TFA). When PG is a basic group, the hydrolysis can be carried out under basic conditions using methods well known to those skilled in the art, for example using sodium or potassium hydroxide.

The compound of formula 10 is treated with the corresponding compound of formula 8 with an amine base, such as triethylamine, in the presence of trimethylacetyl chloride in an ethereal solvent, such as THF, and the intermediate formed by this reaction is then reacted with the intermediate. [In situ] may be prepared by treatment with a chiral oxazolidinone of formula 9. Examples of other oxazolidone that may be used in this method are: (4S)-(−)-4-isopropyl-2-oxazolidinone; (S)-(−)-4-benzyl-2-oxazolidinone; , 5R)-(−)-4-methyl-5-phenyl-2-oxazolidinone; (R)-(+)-4-benzyl-2-oxazolidinone;
(S)-(+)-4-phenyl-2-oxazolidinone; (R)-(−)-4-phenyl-2-oxazolidinone; (R) -4-isopropyl-2-oxazolidinone; and (4S, 5R) -(+)-4-methyl-5-phenyl-2-oxazolidinone; and lithium chloride. Preferably the reaction is carried out with trimethylacetyl chloride and triethylamine in tetrahydrofuran at about −20 ° C. according to literature procedures (see Ho GJ. And Mathre DJ, J. Org. Chem., 1995; 60: 2271-2273). This is carried out by treating the acid of formula 8 and then treating the intermediate produced in such a reaction with oxazolidinone of formula 9 and lithium chloride at about room temperature.

  Alternatively, the compound of formula 10 is an acid chloride obtained from treatment of the corresponding compound of formula 8 with oxalyl chloride in a solvent such as dichloromethane in the presence of dimethylformamide (DMF). Can be prepared by treating. The acid of formula 8 can be prepared from commercially available materials using methods well known to those skilled in the art. These acids may possess one or more chiral centers. The use of citrolenyl bromide and citronellol in the synthesis of such acids is described in Examples 1, 2, and 3 of this application.

Compounds that can be prepared by Method C above include, but are not limited to:
(3S, 5R) -3-Amino-5-methyl-heptanoic acid;
(3S, 5R) -3-Amino-5-methyl-octanoic acid;
(3S, 5R) -3-Amino-5-methyl-nonanoic acid;
(3S, 5R) -3-Amino-5-methyl-decanoic acid;
(3S, 5S) -3-Amino-5-methyl-heptanoic acid;
(3S, 5S) -3-Amino-5-methyl-octanoic acid;
(3S, 5S) -3-Amino-5-methyl-nonanoic acid;
(3S, 5S) -3-Amino-5-methyl-decanoic acid;
(3S) -3-amino-5,5-dimethyl-heptanoic acid;
(3S) -3-amino-5,5-dimethyl-octanoic acid;
(3S) -3-amino-5,5-dimethyl-nonanoic acid;
(3S) -3-amino-5,5-dimethyl-decanoic acid;
(3S, 5R) -3-Amino-7-cyclopropyl-5-methyl-heptanoic acid;
(3S, 5R) -3-Amino-7-cyclobutyl-5-methyl-heptanoic acid;
(3S, 5R) -3-Amino-7-cyclopentyl-5-methyl-heptanoic acid;
(3S, 5R) -3-Amino-7-cyclohexyl-5-methyl-heptanoic acid;
(3S, 5S) -3-Amino-7-cyclopropyl-5-methyl-heptanoic acid;
(3S, 5S) -3-Amino-7-cyclobutyl-5-methyl-heptanoic acid;
(3S, 5S) -3-Amino-7-cyclopentyl-5-methyl-heptanoic acid;
(3S, 5S) -3-Amino-7-cyclohexyl-5-methyl-heptanoic acid.

Alternatively, with reference to the following reaction scheme (Method D), a compound of formula 11 is treated with a suitable acid (eg, trifluoroacetic acid (TFA) if a t-butyl ester is used) to give a compound of formula 14 This yields the corresponding compound, which is then subjected to a Curtius rearrangement (where R ₅ is as above) to yield the corresponding compound of formula 15 (for a description of this approach, see Arvanitis et al , J. Chem. Soc. Perkin Trans 1., 1998, 521). Further hydrolysis of the imide group (to produce the corresponding compound of formula 16) and the carbamate group yields the desired beta amino acid of formula II.

Compound 16 is obtained from compound 15 in the same manner as described above for the conversion of the compound of formula 11 to the compound of formula 12. Compounds of formula 17 can be prepared by treatment with a strong acid such as hydrochloric acid, or a strong base such as sodium or potassium hydroxide, or R ₅ is benzyl under hydrogen atmosphere using palladium on carbon in ethanol or THF. Or in the case of p-methoxybenzyl, it can be prepared from the corresponding compound of formula 16 by hydrogenolysis conditions. This approach of preserving stereochemistry about the chiral center in the compound of formula 11 that is also present in the product of formula II is described in Example 4 of this application.

Compounds that can be produced by this method include, but are not limited to:
(2R, 4R) -2-aminomethyl-4-methyl-hexanoic acid;
(2R, 4R) -2-aminomethyl-4-methyl-heptanoic acid;
(2R, 4R) -2-aminomethyl-4-methyl-octanoic acid;
(2R, 4R) -2-aminomethyl-4-methyl-nonanoic acid;
(2R, 4R) -2-aminomethyl-4-methyl-decanoic acid;
(2R, 4S) -2-aminomethyl-4-methyl-hexanoic acid;
(2R, 4S) -2-aminomethyl-4-methyl-heptanoic acid;
(2R, 4S) -2-aminomethyl-4-methyl-octanoic acid;
(2R, 4S) -2-aminomethyl-4-methyl-nonanoic acid;
(2R, 4S) -2-aminomethyl-4-methyl-decanoic acid;
(2R, 4S) -2-aminomethyl-6-cyclopropyl-4-methyl-hexanoic acid;
(2R, 4S) -2-aminomethyl-6-cyclobutyl-4-methyl-hexanoic acid;
(2R, 4S) -2-aminomethyl-6-cyclopentyl-4-methyl-hexanoic acid;
(2R, 4S) -2-Aminomethyl-6-cyclohexyl-4-methyl-hexanoic acid.

  Other alternative approaches to synthesize α-substituted β-amino acids that can be utilized to prepare compounds of the present invention include Juristi et al Tetrahedron Asymm., 7, (8), as shown in Method E below. 1996, 2233 and Seebach et al, Eur. J. Org. Chem., 1999, 335, or Arvanitis et al, J. Chem. Soc. Perkin Trans 1., 1998, 521.

Method F below illustrates an alternative method of preparing compounds of formula II.

  According to the method disclosed by Hoffman la Roche (FR 1377736 19641106), compounds of formula 3 can be prepared from unsaturated cyanoesters of formula 2 by reduction and hydrolysis. Next, cyanoester 2 can be prepared by Knoevenagel condensation of aldehyde 1 with cyanoacetate (eg Paine, J.B .; Woodward, R.B .; Dolphin, D., J. Org. Chem. 1976, 41, 2826). The aldehydes of formula 1 can be prepared from commercially available materials by methods known to those skilled in the art.

  Compounds of formula III and IV can be prepared using procedures analogous to those of Method F that will be apparent to those skilled in the art. When synthesizing a compound of formula III, the starting material should be a compound similar to formula 1 in Method M, but in this case the hydrogen bonded to the carbonyl group in formula 1 is replaced by a methyl group.

The use of chiral imines to obtain β-amino acids, as exemplified in Method G below, has been previously described (see eg Tang, TP; Ellman, JAJ Org. Chem. 1999, 64, 12-13). .

  The final step in the above scheme is the hydrolysis of both the sulfonamide and ester groups. This reaction is generally carried out using a strong acid such as hydrochloric acid, hydrobromic acid or sulfuric acid in a solvent such as water or dioxane, or a mixture of water and dioxane, at a temperature of about 20 ° C to about 50 ° C. .

Preparation of the compounds of the present invention not specifically described in the foregoing experimental section can be accomplished using combinations of the reactions described above that will be apparent to those skilled in the art.
In each of the reactions discussed or exemplified above, pressure is not critical unless otherwise noted. A pressure of about 0.5 atmospheric pressure to about 5 atmospheric pressure is generally acceptable, and ambient pressure, ie, about 1 atmospheric pressure, is selected for convenience.

Compounds of formula I, IA, IA-1, IA-2, IB, IC, II, IIA, III or IV, and intermediates shown in the above reaction scheme can be prepared by conventional techniques, for example by recrystallization or It can be isolated and purified by chromatographic separation.
The ability of a compound of the invention to bind to the α2δ-subunit of the calcium channel can be determined using the following binding assay.

A radioligand binding assay using [ ³ H] -gabapentin and α2δ-subunit from porcine brain tissue was used (Gee, Nicolas S et al. “The novel anticonvulsant drug, gabapentin (Neurontin), binds to the α2δ subunit. of a calcium channel ”. J. Biol. Chem. (1996), 271 (10), 5768-76). The compounds of the present invention bind with nanomolar to micromolar affinity for α2δ protein. For example, R-3-amino-5,9-dimethyl-decanoic acid binds to α2δ protein with an affinity of 527 nM and (3S, 5S) -3-amino-5-methyl-octanoic acid has an affinity of 1 uM. (2R, 4R) -2-aminomethyl-4-methylheptanoic acid binds with an affinity of 29 nM and 2-aminomethyl-4,4-dimethyl-heptanoic acid has an affinity of 83 nM Join with.

  The in vivo activity of the compounds of the invention can be determined in animal models (eg Sluka, K., et al., “Unilateral Intramuscular Injections Of Acidic Saline Produce A Bilateral, Long-Lasting Hyperalgesia,” Muscle Nerve 24: 37- 46 (2001); Dixon, W., “Efficient analysis of experimental observations,” Ann Rev Pharmacol Toxicol 20: 441-462, (1980); Randall LO and Selitto JJ, “A Method For Measurement Of Analgesic Activity On Inflamed Tissue, ”Arch. Int. Pharmacodyn ,; 4: 409-419, (1957); Hargreaves K., Dubner R., Brown F., Flores C., and Joris J.“ A New And Sensitive Method For Measuring Thermal Nociception In Cutaneous Hyperalgesia, ”Pain. 32: 77-88 (1988) (hyperalgesia)). See also Vogel JR, Beer B, and Clody DE, “A Simple And Reliable Conflict Procedure For Testing Anti-Anxiety Agents,” Psychopharmacologia 21: 1-7 (1971) (anxiety).

  The compounds of the invention and their pharmaceutically acceptable salts can be administered to mammals by oral, parenteral (eg, subcutaneous, intravenous, intramuscular, intrathoracic and infusion techniques), rectal, buccal or intranasal routes. .

  The novel compounds of the present invention are administered by any of the routes previously indicated, alone or in combination with a pharmaceutically acceptable carrier or diluent, and such administration can be carried out once or multiple times. Can be performed on administration. In particular, the novel therapeutic agents of the present invention are administered in a wide variety of different dosage forms, i.e. they are tablets, capsules, lozenges, troches, hard candy, suppositories, jelly, gels, pastes, ointments, aqueous suspensions. Can be combined with various pharmaceutically acceptable inert carriers in the form of injection solutions, elixirs, syrups and the like. Such carriers include solid diluents or fillers, sterile aqueous media and various non-toxic organic solvents. Furthermore, the oral pharmaceutical composition can be suitably sweetened and / or flavored. In general, the weight ratio of the novel compounds of this invention ranges from about 1: 6 to about 2: 1, preferably from about 1: 4 to about 1: 1.

  For oral administration, tablets containing various excipients such as microcrystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine can be combined with various disintegrants such as starch (preferably corn starch, potato starch). Or tapioca starch), alginic acid and certain complex silicates can be used together with particulate binders such as polyvinylpyrrolidone, sucrose, gelatin and gum arabic. In addition, lubricants such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for tableting purposes. A similar type of solid composition can also be used as a filler in gelatin capsules. Preferred materials in this context also include lactose, lactose, and high molecular weight polyethylene glycols. When aqueous suspensions and / or elixirs are desired for oral administration, the active ingredients are various sweetening or flavoring agents, coloring substances or dyes, and if so desired, emulsifiers and / or suspending agents. Can also be combined with diluents such as water, ethanol, propylene glycol, glycerin and various similar combinations thereof.

  For parenteral administration, solutions of the compounds of the invention in sesame oil or peanut oil or in aqueous propylene glycol may be used. The aqueous solution should be appropriately buffered (preferably above pH 8), if necessary, and the liquid diluent should first be made isotonic. These aqueous solutions are suitable for intravenous injection purposes. Oily solutions are suitable for intra-articular, intramuscular and subcutaneous injection purposes. The preparation of all these solutions under sterile conditions is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art.

  For intranasal administration or administration by inhalation, the novel compounds of the invention may be in the form of a solution or suspension from a pump spray container that is squeezed or pumped by the patient, or a suitable propellant, such as Conveniently delivered as an aerosol spray from a pressurized container or nebulizer with the use of dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve to deliver a metered amount. A pressurized container or nebulizer may contain a solution or suspension of the active compound. Capsules and cartridges (eg, made from gelatin) for use in inhalers or dispensers can be formulated containing a powder mix of the compound of the invention and a suitable powder base such as lactose or starch. Formulations of active compounds of the invention for the treatment of such conditions in the average adult are preferably arranged so that each measured dose or aerosol “puff” contains 20 μg to 1000 μg of active compound. It is done. The overall daily dose with an aerosol is in the range 100 μg to 10 mg. Administration may be several times daily, for example 2, 3, 4 or 8 times, giving for example, 1, 2 or 3 doses each time.

  The compounds of the present invention can be prepared and administered in a wide variety of oral and parenteral dosage forms. The compounds of the invention can therefore be administered by injection, i.e. intravenously, intramuscularly, intradermally, subcutaneously, intraduodenum or intraperitoneally. Furthermore, the compounds of the invention can be administered by inhalation, for example intranasally. Furthermore, the compounds of the invention can be administered transdermally. The following dosage forms are active ingredients as compounds of formula I, IA, IA-1, IA-2, IB, IC, II, IIA, III or IV or the corresponding pharmaceutically acceptable of such compounds It will be apparent to those skilled in the art that salts can be included.

  For pharmaceutical compositions from the compounds of the present invention, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier can be one or more substances which may also act as diluents, flavoring agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material. In powders, the carrier is a finely divided solid that is in a mixture with the finely divided active component. In tablets, the active ingredients are mixed with the carrier having the necessary binding properties in the appropriate proportions and compressed into the desired shape and size.

  Powders and tablets preferably contain 5 or 10 to about 70% active compound. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth gum, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like. The term “preparation” is a formulation of an active compound with an encapsulating material as one carrier that provides a capsule in which the active ingredient with or without another carrier is surrounded by and thus associated with one carrier. Intended to include objects. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.

  For the preparation of suppositories, a low melting wax such as a mixture of fatty acid glycerides or cocoa butter is first melted and, when stirred, the active ingredient is homogeneously dispersed therein. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool and thereby solidify.

  Liquid form preparations include solutions, suspensions, and emulsions, for example, water, aqueous propylene glycol solutions. For parenteral injection, liquid preparations can be formulated in solution in aqueous polyethylene glycol solution. Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizers, and thickening agents as desired. Aqueous suspensions suitable for oral use are made by dispersing the finely divided active ingredient in water together with viscous substances such as natural or synthetic rubbers, resins, methylcellulose, sodium carboxymethylcellulose and other well known suspending agents. Can be done.

  Liquid preparations for oral administration also include solid form preparations that are intended to be converted, shortly before use. Such liquid forms include solutions, suspensions and emulsions. These preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and synthetic sweeteners, dispersants, thickeners, solubilizers, and the like.

  The pharmaceutical preparation is preferably in unit dosage form. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component. A unit dosage form is a packaged preparation, the package containing discrete quantities of preparation, such as packed tablets, capsules, and powders in vials or ampoules. Furthermore, the unit dosage form can be a capsule, tablet, cachet or lozenge itself, or it can be any suitable number of these in packaging form.

  The amount of active ingredient in a unit dose preparation can be varied or adjusted from 0.01 mg to 1 g, depending on the particular application and efficacy of the active ingredient. For medical use, the drug can be administered three times daily, for example as a 100 or 300 mg capsule. The composition may also contain other compatible therapeutic agents if desired.

  For therapeutic use, the compounds utilized in the pharmaceutical methods of the invention are administered at an initial dosage of about 0.1 gm to about 1 g per day. However, the dosage can vary depending on the requirements of the patient, the severity of the condition being treated, as well as the compound being used. Determination of the proper dosage for a particular situation is within the skill of the art. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached. For convenience, the total daily dosage may be divided and administered during the day, if desired.

  The following examples illustrate the preparation of compounds of the present invention. They are not meant to be scope limitations. Melting points are not corrected. NMR data is reported in parts per million and is referred to as the deuterium lock signal from the sample solvent.

Example
Example 1. Hydrochloric acid (3S, 5R) -3-amino-5-methyl-octanoic acid
(R) -2,6-Dimethyl-non-2-ene. LiCl (4.3 g) was added to (S) -citronellyl bromide (50 g, 0.228 mol) in THF (800 mL) at 0 ° C. followed by CuCl ₂ (6.8 g). After 30 minutes, methylmagnesium chloride (152 mL of a 3M solution in THF, Aldrich) was added and the solution was allowed to warm to room temperature. After 10 hours, the solution was cooled to 0 ° C. and a saturated aqueous solution of ammonium chloride was carefully added. The resulting two layers were separated and the aqueous phase was extracted with ether. The combined organic phases were dried (MgSO ₄ ) and concentrated to give (R) -2,6-dimethyl-non-2-ene (32 g, 93%). Used without further purification.

(R) -4-Methyl-heptanoic acid. (R) -2,6-Dimethyl-non-2-ene (20 g, 0.13 mol) in acetone (433 mL) was added to CrO in H ₂ SO ₄ (33 mL) / H ₂ O (146 mL). A solution of ₃ (39 g, 0.39 mol) was added over 50 minutes. After 6 hours, an additional amount of CrO ₃ (26 g, 0.26 mol) in H ₂ SO ₄ (22 mL) / H ₂ O (100 mL) was added. After 12 hours, the solution was washed with brine and the solution was extracted with ether. The combined organic phases were dried (MgSO ₄ ) and concentrated. Flash chromatography (6: 1 to 2: 1 hexane / EtOAc gradient) gave (R) -4-methyl-heptanoic acid as an oil (12.1 g, 65%). MS, m / z (relative intensity): 143 [MH, 100%];

(4R, 5S) -4-Methyl-3-((R) -4-methyl-heptanoyl) -5-phenyl-oxazolidin-2-one. To (R) -4-methyl-heptanoic acid (19 g, 0.132 mol) and triethylamine (49.9 g, 0.494 mol) in THF (500 mL) at 0 ° C. was added trimethylacetyl chloride (20 g, 0.17 mol). Added. After 1 hour, LiCl (7.1 g, 0.17 mol) was added followed by (4R, 5S)-(+)-4-methyl-5-phenyl-2-oxazolidinone (30 g, 0.17 mol). The mixture was warmed to room temperature and after 16 hours the filtrate was removed by filtration and the solution was concentrated under reduced pressure. Flash chromatography (7: 1 hexane / EtOAc) gave (4R, 5S) -4-methyl-3-((R) -4-methyl-heptanoyl) -5-phenyl-oxazolidine-2-one as an oil. (31.5 g, 79%). [Α] _D = + 5.5 (c1 in CHCl ₃ ). MS, m / z (relative intensity): 304 [M + H, 100%];

(3S, 5R) -5-methyl-3-((4R, 5S) -4-methyl-2-oxo-5-phenyl-oxazolidine-3-carbonyl) -octanoic acid tert-butyl ester. To (4R, 5S) -4-methyl-3-((R) -4-methyl-heptanoyl) -5-phenyl-oxazolidin-2-one (12.1 g, 0.04 mol) in THF (200 mL)- At 50 ° C., sodium bis (trimethylsilyl) amide (48 mL of 1 M solution in THF) was added. After 30 minutes, t-butyl bromoacetate (15.6 g, 0.08 mol) was added. The solution was stirred at −50 ° C. for 4 hours and then warmed to room temperature. After 16 hours, a saturated aqueous solution of ammonium chloride was added and the two phases were separated. The aqueous phase was extracted with ether and the combined organic phases were dried (MgSO ₄ ) and concentrated. By flash chromatography (9: 1 hexane / EtOAc), (3S, 5R) -5-methyl-3-((4R, 5S) -4-methyl-2-oxo-5-phenyl-oxazolidine-3-carbonyl) -Octanoic acid tert-butyl ester was obtained as a white solid (12 g, 72%). [Α] _D = + 30.2 (c1 in CHCl ₃ ).

(S) -2-((R) -2-Methyl-phenyl) -succinic acid 4-tert-butyl ester. (3S, 5R) -5-methyl-3-((4R, 5S) -4-methyl-2-oxo-5-phenyl-oxazolidine-3-in H ₂ O (73 mL) and THF (244 mL). To a carbonyl) -octanoic acid tert-butyl ester (10.8 g, 0.025 mol) was added a premixed solution of LiOH (0.8 M solution 51.2 mL) and H ₂ O ₂ (30% solution 14.6 mL) at 0 ° C. After 4 hours, an additional 12.8 mL LiOH (0.8 M solution) and 3.65 mL H ₂ O ₂ (30% solution) were added. After 30 minutes, sodium bisulfite (7 g), sodium sulfite (13 g) and water (60 mL) were added, followed by hexane (100 mL) and ether (100 mL). The two layers were separated and the aqueous layer was extracted with ether. The combined organic phases were concentrated to an oil that was dissolved in heptane (300 mL). The resulting solid was filtered off and the filtrate was dried (MgSO ₄ ), concentrated and (S) -2-((R) -2-methyl-phenyl) -succinic acid 4-tert-butyl ester (6 g, 93%), which was used immediately without further purification. MS, m / z (relative intensity): 257 [M + H, 100%].

(3S, 5R) -3-Benzodioxycarbonylamino-5-methyl-octanoic acid tert-butyl ester. Of (S) -2-((R) -2-methyl-phenyl) -succinic acid 4-tert-butyl ester (6.0 g, 23.22 mmol) and triethylamine (3.64 mL, 26.19 mmol) in toluene (200 mL). The solution was treated with diphenylphosphoryl azide (5.0 mL, 23.22 mmol) and stirred at room temperature for 0.5 hour. The reaction mixture was then heated at reflux for 3 hours, cooled briefly, then benzyl alcohol was added (7.2 mL, 69.7 mmol) and the solution was heated for an additional 3 hours. After the reaction mixture was allowed to cool, it was diluted with ethyl ether (200 mL) and the combined organic phases were subsequently washed with saturated NaHCO ₃ and brine and dried (Na ₂ SO ₄ ). The concentrated organic component was purified by chromatography (MPLC) eluting with 8: 1 hexane: ethyl acetate to give (3S, 5R) -3-benzoxycarbonylamino-5-methyl-octanoic acid tert-butyl ester. Obtained (6.4 g, 75.8%). MS: M + 1: 364.2, 308.2.

(3S, 5R) -3-Amino-5-methyl-octanoic acid tert-butyl ester. A solution of (3S, 5R) -3-benzoxycarbonylamino-5-methyl-octanoic acid tert-butyl ester (2.14 g, 5.88 mmol) in THF (50 mL) was added to Pd / C (0.2 g) and 50 Treated with psi of H ₂ for 2 hours. The reaction mixture was then filtered and concentrated to an oil in vacuo to give (3S, 5R) -3-amino-5-methyl-octanoic acid tert-butyl ester in quantitative yield. MS: M + 1: 230.2, 174.1.

Hydrochloric acid (3S, 5R) -3-amino-5-methyl-octanoic acid. A slurry of (3S, 5R) -3-amino-5-methyl-octanoic acid tert-butyl ester (2.59 g, 11.3 mmol) in 6 N HCl (100 mL) was heated at reflux for 18 hours and cooled. And filtered over Celite. The filtrate was concentrated in vacuo to 25 mL and the resulting crystals were collected and dried to give hydrochloric acid (3S, 5R) -3-amino-5-methyl-octanoic acid, mp 142.5-142.7 ° C. (1.2 g, 50.56%). A secondary yield (0.91 g) was obtained from the filtrate. Analytical calculated values for C ₉ H ₁₉ NO ₂ .HCl: C: 51.55, H: 9.61, N: 6.68, Cl: 16.91. Found: C: 51.69, H: 9.72, N: 6.56, Cl: 16.63. MS: M + 1: 174.1.

(3S, 5R) -3-Amino-5-methyl-octanoic acid hydrochloride. 5.3 g of 2S- (2R-methyl-pentyl) -succinic acid-4-tert-butyl ester contained in 30 mL of methyl tert-butyl ether was added at room temperature with 3.5 mL of triethylamine followed by 6.4 g of Reaction with diphenylphosphoryl chloride. The reaction was allowed to exotherm to 45 ° C. and stirred for at least 4 hours, after which the reaction mixture was allowed to cool to room temperature and left to stand during this time. The lower layer is discarded and the upper layer is washed with water and then with dilute hydrochloric acid solution. The upper layer is then combined with 10 mL of 6 N HCl aqueous solution and stirred at 45-65 ° C. The reaction mixture is concentrated to about 10-14 mL by vacuum distillation and crystallized while cooling to about 5 ° C. After collecting the product by filtration, the product is washed with toluene and reslurried in toluene. The product is dried by heating under vacuum to give 2.9 g (67%) of white crystalline product. The product can be recrystallized from aqueous HCl. Melting point 137 ° C.

Example 2 (3S, 5R) -Amino-5-methyl-heptanoic acid
Methanesulfonic acid (S) -3,7-dimethyl-oct-6-enyl ester. Chloride in CH ₂ Cl ₂ (200 mL) at 0 ° C. to S-(−)-citronellol (42.8 g, 0.274 mol) and triethylamine (91 mL, 0.657 mol) in CH ₂ Cl ₂ (800 mL). Methanesulfonyl (26 mL, 0.329 mol) was added. After 2 hours at 0 ° C., the solution was washed with 1 N HCl and then with brine. The organic phase was dried (MgSO ₄ ) and concentrated to give the title compound as an oil (60.5 g, 94%), which was used without further purification. MS, m / z (relative intensity): 139 [100%], 143 [100%].

(R) -2,6-Dimethyl-oct-2-ene. To the methanesulfonic acid (S) -3,7-dimethyl-oct-6-enyl ester (60 g, 0.256 mol) in THF (1 L) was added lithium aluminum hydride (3.8 g, 0.128 mol). After 7 hours, an additional 3.8 g of lithium aluminum hydride was added and the solution was allowed to warm to room temperature. After 18 hours, an additional 3.8 g of lithium aluminum hydride was added. After an additional 21 hours, the reaction was carefully quenched with 1 N citric acid and the solution was further diluted with brine. The resulting two phases were separated and the organic phase was dried (MgSO ₄ ) and concentrated to give the title compound as an oil that was used without further purification. MS, m / z (relative intensity): 139 [100%].

(R) -4-Methyl-hexanoic acid. The acid was obtained as an oil (9.3 g, 56%) using a procedure similar to the synthesis of (R) -4-methyl-heptanoic acid. IR (film) 2963, 2931, 2877, 2675, 1107, 1461, 1414 cm ⁻¹ ; MS, m / z (relative strength): 129 [MH, 100%];

(4R, 5S) -4-Methyl-3-((R) -4-methyl-hexanoyl) -5-phenyl-oxazolidin-2-one. The title compound was obtained as an oil using a procedure similar to the synthesis of (4R, 5S) -4-methyl-3-((R) -4-methyl-heptanoyl) -5-phenyl-oxazolidin-2-one. (35.7 g, 95%). MS, m / z (relative intensity): 290 [M + H, 100%];

(3S, 5R) -5-methyl-3- [1-((4R, 5S) -4-methyl-2-oxo-5-phenyl-oxazolidin-3-yl) -methanoyl] -heptanoic acid tert-butyl ester . Similar procedure to the preparation of (3S, 5R) -5-methyl-3-((4R, 5S) -4-methyl-2-oxo-5-phenyl-oxazolidine-3-carbonyl) -octanoic acid tert-butyl ester The title compound was obtained as an oil (7.48 g; 31%). IR (film) 2967, 2934, 1770, 1716, 1696, 1344, 1148, 1121, 1068, 1037, 947 cm ^-1 ; MS, m / z (relative strength): 178 [100%], 169 [100%] [Α] _D = +21.6 (c1 in CHCl ₃ );

(S) -2-((R) -2-Methyl-butyl) -succinic acid 4-tert-butyl ester. (3S, 5R) -5-methyl-3- [1-((4R, 5S) -4-methyl-2-oxo-5-phenyl-oxazolidine in H ₂ O (53 mL) and THF (176 mL) -3-yl) -methanoyl] -heptanoic acid tert-butyl ester (7.26 g, 0.018 mol) in LiOH (0.8 M solution 37 mL) and H ₂ O ₂ (30% solution 10.57 mL) at 0 ° C. The mixed solution was added and the solution was warmed to room temperature. After 2 hours, sodium bisulfite (7 g), sodium sulfite (13 g) and water (60 mL) were added, the two phases were separated and the aqueous layer was extracted with ether. The combined organic phase was concentrated to an oil that was dissolved in heptane (200 mL). The resulting solid was filtered off and the filtrate was dried (MgSO ₄ ) and concentrated to give the title compound as an oil (4.4 g), which was used without further purification. MS, m / z (relative intensity): 243 [100%];

(3S, 5R) -3-Benzioxycarbonylamino-5-methyl-heptanoic acid tert-butyl ester. This compound was prepared as described above starting with (S) -2-((R) -2-methyl-butyl) -succinic acid 4-tert-butyl ester to give (3S, 5R) -3- Bendioxycarbonylamino-5-methyl-heptanoic acid tert-butyl ester was obtained as an oil (yield 73.3%).

(3S, 5R) -Amino-5-methyl-heptanoic acid tert-butyl ester. Instead of (3S, 5R) -3-benzdioxycarbonylamino-5-methyl-octanoic acid tert-butyl ester, starting with (3S, 5R) -3-benzoxycarbonylamino-5-methyl-heptanoic acid, This compound was prepared as above to give the title compound.

Ｃ₈Ｈ₁₇ＮＯ₂・ＨＣｌに関する分析計算値：Ｃ：48.65、Ｈ：9.29、Ｎ：7.09、Ｃｌ：17.95。実測値：Ｃ：48.61、Ｈ：9.10、Ｎ：7.27、Ｃｌ：17.87。ＭＳ：Ｍ＋１：160.2。 Hydrochloric acid (3S, 5R) -amino-5-methyl-heptanoic acid. A slurry of (3S, 5R) -amino-5-methyl-heptanoic acid tert-butyl ester (1.44 g, 6.69 mmol) in 3 N HCl (100 mL) was heated at reflux for 3 hours, cooled and cooled to celite. Filtered hot above, concentrated and dried. The resulting solid was triturated in ethyl ether to give hydrochloric acid (3S, 5R) -3-amino-5-methyl-heptanoic acid (0.95 g, 85%). Melting point 126.3-128.3 ° C.

Analytical calculated values for C ₈ H ₁₇ NO ₂ .HCl: C: 48.65, H: 9.29, N: 7.09, Cl: 17.95. Found: C: 48.61, H: 9.10, N: 7.27, Cl: 17.87. MS: M + 1: 160.2.

ＣｒＯ₃ 26.7 g、Ｈ₂ＳＯ₄ 23 ｍＬを併合し、Ｈ₂Ｏで希釈して100 mLとすることにより、ジョーンズ試薬を調製した。 Example 3 (3S, 5R) -3-Amino-5-methyl-nonanoic acid
(R) -4-Methyl-octanoic acid. Lithium chloride (0.39 g, 9.12 mmol) and copper (I) chloride (0.61 g, 4.56 mmol) were combined in 45 mL of THF at ambient temperature, stirred for 15 minutes, then cooled to 0 ° C., at which point Ethyl magnesium bromide (1 M solution in THF, 45 mL, 45 mmol) was added. Bromo (S) -citronellyl bromide (5.0 g, 22.8 mmol) was added dropwise and the solution was slowly warmed to room temperature with stirring overnight. The reaction was quenched by carefully adding saturated aqueous NH ₄ Cl and stirred for 30 minutes with Et ₂ O and saturated aqueous NH ₄ Cl. The phases were separated and the organic phase was dried (MgSO ₄ ) and concentrated. Crude (R) -2,6-dimethyl-dec-2-ene was used without further purification. To a solution of (R) -2,6-dimethyl-dec-2-ene (3.8 g, 22.8 mmol) in 50 mL of acetone, Jones reagent (2.7 M in aqueous H ₂ SO ₄ solution, 40 mL, 108 mmol) was added. The solution was gradually warmed to room temperature with stirring overnight. The mixture was partitioned between Et ₂ O and H ₂ O, the phases were separated and the organic phase was washed with brine, dried (MgSO ₄ ) and concentrated. The residue was purified by flash chromatography (8: 1 hexane: EtOAc) to give 2.14 g (59%) of the title compound as a colorless oil: LRMS: m / z 156.9 (M +);

Jones reagent was prepared by combining 26.7 g of CrO _{3 and} 23 mL of H ₂ SO ₄ and diluting to 100 mL with H ₂ O.

粗生成物をさらに精製せずに用いた。 (4R, 5S) -4-Methyl-3-((R) -4-methyl-octanoyl) -5-phenyl-oxazolidin-2-one. To (R) -4-methyl-octanoic acid (2.14 g, 13.5 mmol) in CH ₂ Cl ₂ (25 mL) was added 3 drops of DMF at 0 ° C., followed by oxalyl chloride (1.42 mL, 16.2 mmol) was added resulting in vigorous gas evolution. The solution was immediately warmed to ambient temperature, stirred for 30 minutes and concentrated. Meanwhile, n-butyllithium (1.6 M solution in hexane, 9.3 mL, 14.9 mmol) was added dropwise at −78 ° C. to a solution of oxazolidinone (2.64 g, 14.9 mmol) in 40 mL of THF. The mixture was stirred for 10 minutes, at which point the acid in 10 mL of THF was added dropwise. The reaction was stirred at −78 ° C. for 30 minutes, then immediately warmed to ambient temperature and quenched with saturated NH ₄ Cl. The mixture was partitioned between Et ₂ O and saturated aqueous NH ₄ Cl, the phases were separated, the organic phase was dried (MgSO ₄ ) and concentrated to give 3.2 g of the title compound as a colorless oil. LRMS: m / z 318.2 (M +);

The crude product was used without further purification.

Ｃ₂₅Ｈ₃₇ＮＯ₅に関する分析計算値：Ｃ：69.58、Ｈ：8.64、Ｎ：3.25。実測値：Ｃ：69.37、Ｈ：8.68、Ｎ：3.05。 (3S, 5R) -5-Methyl-3-((4R, 5S) -4-methyl-2-oxo-5-phenyl-oxazolidine-3-carbonyl) -nonanoic acid tert-butyl ester. To a solution of diisopropylpyramine (1.8 mL, 12.6 mmol) in 30 mL of THF at −78 ° C. was added n-butyllithium (1.6 M solution in hexane, 7.6 mL, 12.1 mmol) and the mixture was stirred for 10 minutes. At this point, (4R, 5S) -4-methyl-3-((R) -4-methyl-octanoyl) -5-phenyl-oxazolidin-2-one (3.2 g, 10.1 mmol) in 10 mL of THF was added. It was dripped. The solution was stirred for 30 minutes, t-butyl bromoacetate (1.8 mL, 12.1 mmol) was quickly added dropwise at −50 ° C., and the mixture was gradually warmed to 10 ° C. over 3 hours. The mixture was partitioned between Et ₂ O and saturated aqueous NH ₄ Cl, the phases were separated, the organic phase was dried (MgSO ₄ ) and concentrated. The residue was purified by flash chromatography (16: 1 to 8: 1 hexane: EtOAc) to give 2.65 g (61%) of the title compound as a colorless crystalline solid. Melting point = 84-86 ° C. [Α] _D ²³ +17.1 (c = 1.00 in CHCl ₃ ):

C ₂₅ H ₃₇ NO ₅ relates Calcd: C: 69.58, H: 8.64 , N: 3.25. Found: C: 69.37, H: 8.68, N: 3.05.

(S) -2-((R) -2-Methyl-hexyl) -succinic acid 4-tert-butyl ester. (3S, 5R) -5-methyl-3-((4R, 5S) -4-methyl-2-oxo-5-phenyl-oxazolidine-3-carbonyl) -nonanoic acid tert-butyl ester (2.65) in 20 mL of THF g, 6.14 mmol) at 0 ° C., precooling (0 ° C.) of LiOH monohydrate (1.0 g, 23.8 mmol) and hydrogen peroxide (5.0 mL of 30 wt% aqueous solution) in 10 mL of H ₂ O The solution was added. The mixture was stirred vigorously for 90 minutes, then warmed to ambient temperature and stirred for 90 minutes. The reaction was quenched by the addition of 10% NaHSO ₃ (aq) and then extracted with Et ₂ O. The phases were separated and the organic phase was washed with brine, dried (MgSO ₄ ) and concentrated. The title compound was used without purification.

(3S, 5R) -3-Benzyloxycarbonylamino-5-methyl-nonanoic acid tert-butyl ester. (S) -2-((R) -2-methylhexyl) -succinic acid 4-tert instead of (S) -2-((R) -2-methylphenyl) -succinic acid 4-tert-butyl ester Starting with the butyl ester, the compound was prepared as above to give the title compound as an oil (yield 71.6%).

(3S, 5R) -3-Amino-5-methyl-nonanoic acid tert-butyl ester. Instead of (3S, 5R) -3-benzdioxycarbonylamino-5-methyl-octanoic acid tert-butyl ester, (3S, 5R) -3-benzyloxycarbonylamino-5-methyl-nonanoic acid tert-butyl ester Starting, this compound was prepared as described above. Yield = 97%.

Ｃ₁₀Ｈ₂₁ＮＯ₂・ＨＣｌに関する分析計算値：Ｃ：53.68、Ｈ：9.91、Ｎ：6.26、Ｃｌ：15.85。実測値：Ｃ：53.89、Ｈ：10.11、Ｎ：6.13。ＭＳ：Ｍ＋１：188.1。 Hydrochloric acid (3S, 5R) -3-amino-5-methyl-nonanoic acid. A mixture of (3S, 5R) -3-amino-5-methyl-nonanoic acid tert-butyl ester (1.50 g, 6.16 mmol) in 3 N HCl (100 mL) was heated under reflux for 3 h and over celite. Hot filtered and concentrated in vacuo to 30 mL. The resulting crystals were collected, washed with additional 3 N HCl and dried to give the title compound (mp 142.5-143.3 ° C.). An additional yield of 1.03 g (70.4%) was obtained from the filtrate.

Analytical calculated values for C ₁₀ H ₂₁ NO ₂ .HCl: C: 53.68, H: 9.91, N: 6.26, Cl: 15.85. Found: C: 53.89, H: 10.11, N: 6.13. MS: M + 1: 188.1.

Example 4 (2R, 4R) -2-Aminomethyl-4-methyl-heptanoic acid
5R-methyl-3R- (4S-methyl-2-oxo-5R-phenyloxazolidine-3-carbonyl) octanoic acid. Tert-Butyl (3R, 5R) -5-methyl-3-((4S, 5R) -4-methyl-2-oxo-5-phenyl-oxazolidine-3-carbonyl) -octanoate in dichloromethane (150 mL) A solution of the ester (3.9 g, 9.34 mmol) was treated with trifluoroacetic acid (7.21 mL, 93.4 mL) and stirred at ambient temperature for 18 hours. After removing the solvent and reagents in vacuo, the resulting residue was triturated in 100 mL of hexane to give 3.38 g of the title compound (100%). Mp 142-143 ° C. MS M + 1 = 362.1.

[4R-Methyl-2R- (4S-methyl-2-oxo-5R-phenyloxazolidine-3-carbonyl) heptyl] carbamic acid benzyl ester. A solution of 5R-methyl-3R- (4S-methyl-2-oxo-5R-phenyloxazolidine-3-carbonyl) octanoic acid (1.98 g, 5.48 mmol) and triethylamine (0.92 mL, 6.57 mmol) was added to diphenylphosphoryl azide ( 1.2 mL, 5.48 mmol), stirred at ambient temperature for 30 minutes and then heated at reflux for 3 hours. After cooling briefly, the reaction mixture was treated with benzyl alcohol (2.8 mL, 27.4 mmol) and heated at reflux for an additional 3 hours. The reaction mixture was cooled, diluted with ethyl ether (150 mL), washed successively with saturated NaHCO ₃ and brine, dried (MgSO ₄ ) and concentrated in vacuo to an oil. Chromatography (MPLC, eluting with 4: 1 hexane: ethyl acetate) afforded the title compound as an oil (2.0 g, 78.3%). MS M + 1 = 467.1.

2R- (benzyloxycarbonylaminomethyl) -4R-methylheptanoic acid. Of [4R-methyl-2R- (4S-methyl-2-oxo-5R-phenyloxazolidine-3-carbonyl) heptyl] carbamic acid benzyl ester (4.12 g, 8.83 mmol) in 3: 1 THF: water (100 mL). The solution was cooled to 0 ° C. and treated with a mixture of 0.8 N LiOH (17.5 mL, 14 mmol) and 30% H ₂ O ₂ (4.94 mL, 44 mmol). After the reaction mixture was stirred in the cold for 3 hours, it was quenched with a slurry of NaHSO ₃ (2.37 g) and Na ₂ SO ₃ (4.53 g) in water (30 mL) and stirred for 1 hour. The reaction mixture was diluted with ethyl ether (200 mL), partitioned and the organic layer was washed with brine and dried (MgSO ₄ ). The concentrated organic extract was chromatographed (MPLC) and eluted with ethyl acetate to give 1.25 g of 2R- (benzyloxycarbonylaminomethyl) -4R-methylheptanoic acid (46%). MS M + 1 = 308.1.

Ｃ₉Ｈ₁₉ＮＯ₂・0.1 Ｈ₂Ｏに関する分析計算値：Ｃ：61.75、Ｈ：11.06、Ｎ：8.00。実測値：Ｃ：61.85、Ｈ：10.83、Ｎ：8.01。 Hydrochloric acid (2R, 4R) -2-amino-4-methyl-heptanoic acid. A mixture of 2R- (benzyloxycarbonylaminomethyl) -4R-methylheptanoic acid (1.25 g, 4.07 mmol) and Pd / C (20%, 0.11 g) in methanol (50 mL) was hydrogenated at 50 psi for 18 hours. Added. After the catalyst was removed by filtration, the solvent was removed in vacuo and the resulting solid was triturated in ether to give hydrochloric acid (2S, 4R) -2-amino-4-methyl-heptanoic acid (0.28 g, 40% ) Melting point 226.3-228.0 ° C. MS M + 1 = 174.0.

Analytical calculated values for C ₉ H ₁₉ NO ₂ .0.1 H ₂ O: C: 61.75, H: 11.06, N: 8.00. Found: C: 61.85, H: 10.83, N: 8.01.

Example 5 FIG. 2-Aminomethyl-4,4-dimethyl-heptanoic acid hydrochloride
2-cyano 4,4-dimethyl-hepta-2,6-dienoic acid ethyl ester. 2,2-Dimethyl-pent-4-enal (5.0 g, 44 mmol), cyanoacetic acid ethyl ester (5.12 mL, 48 mmol), piperidine (1.3 mL, 14 mmol) and acetic acid (4.52 mL, in 170 mL of toluene) 80 mmol) was heated at reflux in a flask equipped with a Dean-Stark separator for 18 hours. Several mL of water was collected in the trap. The reaction was cooled and washed successively with 1 N HCl, NaHCO ₃ and brine. The organic layer was dried over Na ₂ SO ₄ and concentrated to an oil. The oil was chromatographed and eluted with 20% EtOAc in hexanes to give a total of 8.3 g (91%) of the two combinations.

Ｃ₁₀Ｈ₂₁ＮＯ₂・ＨＣｌに関する分析計算値：Ｃ：53.68、Ｈ：9.91、Ｎ：6.26、Ｃｌ：15.85。実測値：Ｃ：53.83、Ｈ：10.15、Ｎ：6.22、Ｃｌ：15.40。ＭＰ：229.5〜231.0℃。 2-Aminomethyl-4,4-dimethyl-heptanoic acid hydrochloride. 2-cyano 4,4-dimethyl - hepta-2,6-dienone acid ethyl ester (5.88 g, 28 mmol), was dissolved in a mixture of ethanol 91 mL and HCl 6 mL, and treated with PtO ₂ of 0.4 g . The reaction was carried out at room temperature for 15 hours under 100 psi hydrogen pressure. The catalyst was filtered and the filtrate was concentrated to give 3.8 g of the desired product 2-aminomethyl-4,4-dimethyl-heptanoic acid ethyl ester as an oil. MS (APCI): 216.2 (M + 1) ^<+> . This oil was refluxed in 75 mL of 6 N HCl for 18 hours. A precipitate formed during cooling of the reaction. The solid was filtered, washed with additional HCl solution and triturated with ether to give the clean title compound. MS (APCI): 188.1 (M + 1) ^<+> , 186.1 (M-1) ^<+> .

Analytical calculated values for C ₁₀ H ₂₁ NO ₂ .HCl: C: 53.68, H: 9.91, N: 6.26, Cl: 15.85. Found: C: 53.83, H: 10.15, N: 6.22, Cl: 15.40. MP: 229.5-231.0 ° C.

Example 6 (S) -3-Amino-5,5-dimethyl-octanoic acid
3- (4,4-Dimethyl-heptanoyl)-(R) -4-methyl- (S) -5-phenyl-oxazolidin-2-one. A solution of 4,4-dimethyl-heptanoic acid (1.58 g, 10 mmol) and triethylamine (4.6 mL) in 50 mL of THF was cooled to 0 ° C. and treated with 2,2-dimethyl-propionyl chloride (1.36 mL). . After 1 hour, 4R-methyl-5S-phenyl-oxazolidine-2-one (1.95 g, 11 mmol) and lithium chloride (0.47 g, 11 mmol) were added and the mixture was stirred for 18 hours. The precipitate was filtered and washed thoroughly with additional THF. The filtrate was concentrated in vacuo to give an oily solid. This solid was dissolved in 200 mL Et ₂ O, washed successively with saturated NaHCO ₃ , 0.5 N HCl and saturated NaCl, dried (MgSO ₄ ) and concentrated in vacuo to give the title compound as an oil (3.0 g, 95%).

5,5-Dimethyl- (S) -3-((R) -4-methyl-2-oxo-5R-phenyloxazolidine-3-carbonyl) -octanoic acid tert-butyl ester. According to Example 1, 5.07 g (16 mmol) of 3- (4,4-dimethyl-heptanoyl) -4-methyl-5-phenyl-oxazolidine-2-one, 18 mL (1 N, 18 mmol) From NaHMDS solution and 4.72 mL (32 mmol) bromo-acetic acid tert-butyl ester, 3.40 g (49.3%) of the title compound was obtained as a crystalline solid.

(S) -2- (2,2-Dimethyl-pentyl) -succinic acid 4-tert-butyl ester. According to Example 1, 3.4 g (7.9 mmol) of 5,5-dimethyl-3- (4-methyl-2-oxo-5-phenyl-oxazolidine-3-carbonyl) -octanoic acid tert-butyl ester, 16 mL ( 12.8 mmol) 0.8 NLiOH and 4.5 mL 30% H ₂ O ₂ gave 2.42 g (> 100%) of the title compound as an oil.

(S) -3-Benzyloxycarbonylamino-5,5-dimethyl-octanoic acid tert-butyl ester. According to Example 1, 2.14 g of (7.9 mmol) 2- (2,2- dimethyl - phenyl) - succinic acid 4-tert-butyl ester, of 1.7 mL DPPA, from BnOH of 1.1 mL of Et ₃ N and 2.44 mL 1.63 g (54.8% over two steps) of the title compound as an oil.

(S) -3-Amino-5,5-dimethyl-octanoic acid tert-butyl ester. The title compound was obtained according to Example 1 from 1.63 g 3-benzyloxycarbonylamino-5,5-dimethyl-octanoic acid tert-butyl ester and 0.2 g 20% Pd / C.

Ｃ₁₀Ｈ₂₁ＮＯ₂・ＨＣｌに関する分析計算値：Ｃ：53.17、Ｈ：9.92、Ｎ：6.20、Ｃｌ：15.69。実測値：Ｃ：53.19、Ｈ：10.00、Ｎ：6.08、Ｃｌ：15.25。α＝＋20°（ＭｅＯＨ）。ＭＰ：194.2〜195.2℃。 Hydrochloric acid (S) -3-amino-5,5-dimethyl-octanoic acid. According to Example 1, 3-amino-5,5-dimethyl-octanoic acid tert-butyl ester was treated with 3 N HCl to give 286 mg of the title compound as a solid.

Analytical calculated values for C ₁₀ H ₂₁ NO ₂ .HCl: C: 53.17, H: 9.92, N: 6.20, Cl: 15.69. Found: C: 53.19, H: 10.00, N: 6.08, Cl: 15.25. α = + 20 ° (MeOH). MP: 194.2-195.2 ° C.

Ｃ₁₀Ｈ₁₃ＮＯ₂に関する分析計算値：Ｃ：67.02、Ｈ：7.31、Ｎ：7.82。実測値：Ｃ：66.86、Ｈ：7.47、Ｎ：7.70。 Example 7 2-Aminomethyl-3- (1-methyl-cyclopropyl) -propionic acid
2-Cyano-3- (1-methyl-cyclopropyl) -acrylic acid ethyl ester. To 1-methylcyclopropane-methanol (Aldrich, 1.13 mL, 11.6 mmol) in 50 mL of CH ₂ Cl ₂ was added natural alumina (2.5 g) followed by PCC (2.5 g, 11.6 mmol), and Congo. The material was stirred at ambient temperature for 3 hours. The mixture was filtered through a 1 cm plug of silica gel under vacuum and rinsed with Et ₂ O. The filtrate was concentrated to a total volume of about 5 mL. To the residue was added THF (10 mL), ethyl cyanoacetate (1.2 mL, 11.3 mmol), piperidine (5 drops), and finally acetic acid (5 drops). The whole was stirred overnight at ambient temperature and then partitioned between Et ₂ O and saturated aqueous NaHCO ₃ . The phases were separated and the organic phase was washed with brine, dried (MgSO ₄ ) and concentrated. Flash chromatography of the residue (10 → 15% EtOAc / hexane) gave 0.53 g (25%) of the ester as a colorless oil that crystallized on standing. Melting point 35-37 ° C.

Analytical calculated values for C ₁₀ H ₁₃ NO ₂ : C: 67.02, H: 7.31, N: 7.82. Found: C: 66.86, H: 7.47, N: 7.70.

2-Aminomethyl-3- (1-methyl-cyclopropyl) -propionic acid ethyl ester. To 2-cyano-3- (1-methyl-cyclopropyl) -acrylic acid ethyl ester (0.45 g, 2.51 mmol) in 16 mL EtOH: THF (1: 1) was added RaNi (0.4 g), The mixture was hydrogenated in a Parr shaker at 48 psi for 15.5 hours. Pearlman's catalyst (0.5 g) was then added and hydrogenation was continued for another 15 hours. The mixture was filtered and concentrated. Flash chromatography of the residue (2 → 3 → 4 → 5 → 6 → 8% MeOH / CH ₂ Cl ₂ ) gave 0.25 g (54%) of the amino ester as a colorless oil.

2-Aminomethyl-3- (1-methyl-cyclopropyl) -propionic acid. To a solution of 2-aminomethyl-3- (1-methyl-cyclopropyl) -propionic acid ethyl ester (0.25 g, 1.35 mmol) in 10 mL of methanol at 0 ° C. is added 10% aqueous NaOH (10 mL). Added. The mixture was stirred overnight at ambient temperature and then concentrated to remove methanol. The residue was cooled to 0 ° C. and acidified to pH 2 with concentrated HCl. After warming to ambient temperature, the mixture was loaded onto DOWEX-50WX8-100 ion exchange resin and eluted with H ₂ O until neutral with litmus. Elution was continued with 5% aqueous NH ₄ OH (100 mL) and the alkaline fraction was concentrated to give 0.15 g (71%) of the amino acid as a colorless solid.

^*（Ｓ）−３−メチル−ヘキス−４−エノン酸エチルエステルは、文献プロトコール［Hill, R.K.; Soman, R.; Sawada, S., J. Org. Chem., 1972, 37, 3737］に従って、トリエチルオルトアセテートを用いたジョンソン・クライゼン転位により、（Ｓ）−トランス−３−ペンテン−２−オールから調製した［Liang, J.; Hoard, D.W.; Van Khau, V.; Martinelli, M.J.; Moher, E.D.; Moore, R.E.; Tius, M.A. J. Org. Chem., 1999, 64, 1459］。 Example 8 FIG. (3S, 5R) -3-Amino-5-methyl-octanoic acid
(5S) -5-Methyl-octa-2,6-dienoic acid tert-butyl ester. To a solution of (S) -3-methyl-hex-4-enoic acid ethyl ester (1.0 g, 6.4 mmol) in 30 mL of toluene, DIBAH (1.0 M in THF, 6.4 mL) at −78 ° C. for 5 min. It was hung and dropped. The mixture was stirred at −78 ° C. for 45 minutes, at which point 5 drops of methanol were added resulting in vigorous H ₂ evolution. Methanol was added (ca. 5 mL) until no gas evolution was observed. At this point, the cold bath was removed and approximately 5 mL of saturated Na ⁺ K ⁺ tartrate aqueous solution was added. When the mixture reached room temperature, additional saturated aqueous Na ⁺ K ⁺ tartrate and Et ₂ O were added and stirring was continued until the phase was almost clear (about 1 hour). The phases were separated and the organic phase was washed with brine, dried (MgSO ₄ ) and concentrated to a total volume of about 10 mL for volatile events. The crude mixture was combined with an additional batch of aldehyde prepared from 10 mmol ester by the method described above and used without purification. To a suspension of sodium hydride (60% dispersion in mineral oil) in 25 mL of THF, t-butyl-P, P-dimethylphosphonoacetate (3.0 mL, 15 mmol) was added dropwise over 1 hour. , H ₂ evolution was under control. After the addition was complete, the crude aldehyde in toluene (total volume about 20 mL) was quickly added dropwise and the mixture was stirred overnight at ambient temperature. The mixture was partitioned between Et ₂ O and saturated aqueous NH ₄ Cl, the phases were separated, the organic phase was washed with brine, dried (MgSO ₄ ) and concentrated. Flash chromatography of the residue (0 → 3 → 5% EtOAc / hexane) gave 1.0 g (29%, 2 steps) of unsaturated ester as a pale yellow oil.

^* (S) -3-Methyl-hex-4-enoic acid ethyl ester is prepared according to literature protocol [Hill, RK; Soman, R .; Sawada, S., J. Org. Chem., 1972, 37, 3737]. Prepared from (S) -trans-3-penten-2-ol by Johnson Claisen rearrangement using triethylorthoacetate [Liang, J .; Hoard, DW; Van Khau, V .; Martinelli, MJ; Moher Moore, RE; Tius, MAJ Org. Chem., 1999, 64, 1459].

(3R, 5S) -3- [Benzyl- (1-phenyl-ethyl) -amino] -5-methyl-oct-6-enoic acid tert-butyl ester. To a solution of (S)-(−)-N-benzyl-α-methylbenzylamine (0.60 mL, 2.85 mmol) in 9.0 mL THF at −78 ° C., n-butyllithium (1.6 M in hexane, 1.6 mL) was dripped rapidly to give a deep pink color. The mixture was stirred at −78 ° C. for 30 min, at which point (5S) -5-methyl-octa-2,6-dienoic acid tert-butyl ester (0.5 g, 2.38 mmol) in 1.0 mL THF was slowly added. To give a light brown color that became dark after 3 hours. The mixture was stirred at −78 ° C. for 3 hours and then quenched with saturated aqueous NH ₄ Cl. The mixture was allowed to warm to room temperature and stirred overnight, then partitioned between EtOAc and saturated aqueous NH ₄ Cl. The phases were concentrated and the organic phase was dried (MgSO ₄ ) and concentrated. Flash chromatography of the residue (3 → 5% EtOAc / hexane) gave 0.52 g (52%) of the amino ester as a yellow oil.

(3S, 5R) -3-Amino-5-methyl-octanoic acid. Of (3R, 5S) -3- [benzyl- (1-phenyl-ethyl) -amino] -5-methyl-oct-6-enoic acid tert-butyl ester (0.92 g, 2.18 mmol) in 50 mL of MeOH. To the solution was added 20% Pd / C (0.20 g) and the mixture was hydrogenated in a Parr shaker at 48 psi for 23 hours. The mixture was filtered and concentrated. To the crude aminoester in 10 mL CH ₂ Cl ₂ was added 1.0 mL trifluoroacetic acid and the solution was stirred overnight at ambient temperature. The mixture was concentrated, the residue dissolved in H ₂ O in a minimum amount was loaded on DOWEX-50WX8-100 ion exchange resin. The column was eluted with H ₂ O until medieval with litmus, then elution was continued with 5% aqueous NH ₄ OH (100 mL). The alkaline fraction was concentrated to give 0.25 g (66%, 2 steps) of amino acid as an off-white solid.

Example 9 2-Aminomethyl-8-methyl-nonanoic acid 6-Methyl-1-heptanol m / z 202.1 (M + 2-aminomethyl-8-methyl-nonanoic acid was prepared from

2-Aminomethyl-4,8-dimethyl-nonanoic acid
(R) -2,6-Dimethylheptan-1-ol. Magnesium turning (2.04 g, 84 mmol) and iodine crystals were suspended in 5 mL THF for the addition of 1-bromo-3-methylbutane (0.3 mL, net). The mixture was heated to initiate Grignard purification. The remaining 1-bromo-3-methylbutane (8.63 mL, 72 mmol) was diluted in THF (60 mL) and added dropwise. The mixture was stirred at ambient temperature for 2 hours and cooled to -5 ° C. A solution of copper chloride (1.21 g, 9 mmol) and LiCl (0.76 g, 18 mmol) in THF (50 mL) was added dropwise, keeping the temperature below 0 ° C. The resulting mixture was stirred for 20 minutes and (R) -3-bromo-2-methylpropanol in THF (20 mL) was added dropwise, keeping the temperature below 0 ° C. The mixture was allowed to reach ambient temperature gradually overnight. The reaction mixture was quenched with ammonium hydroxide and water. The mixture was diluted with EtOAc and extracted with 3 × 20 mL of EtOAc. The organics were washed with brine, dried (MgSO ₄ ), filtered and concentrated. The residual oil was purified by silica gel chromatography (90/10 hexane / EtOAc) to give 2.67 g of (R) -2,6-dimethylheptan-1-ol.

(R) -1-Iodo-2,6-dimethylheptane. To a mixture of supported triphenylphosphine (6.55 g, 19.67 mmol) in CH ₂ Cl ₂ was added iodine (4.99 g, 19.67 mmol) and imidazole (1.33 g, 19.67 mmol). The mixture was warmed to ambient temperature, stirred for 1 h and cooled to 0 ° C. for the dropwise addition of (R) -2,6-dimethylheptan-1-ol in CH ₂ Cl ₂ (5 mL). The mixture was allowed to reach ambient temperature and stirred for 1 h, at which point it was filtered through a pad of celite and the solid was washed with CH ₂ Cl ₂ . The filtrate was concentrated and the crude product was purified by silica gel chromatography to give (R) -1-iodo-2,6-dimethylheptane (2.44 g).

(4R) -4,8-Dimethylnonanoic acid t-butyl ester. To diisopropylamine (0.827 mL, 5.9 mmol) in THF (8 mL) was added nBuLi (2.65 mL of a 2.6 M solution in pentane) at −78 ° C. The solution was stirred at −78 ° C. for 30 minutes before t-butyl acetate (0.8 mL, 5.9 mmol) was added. The mixture was stirred at −78 ° C. for 2 hours, then (R) -1-iodo-2,6-dimethylheptane (0.3 g, 1.18 mmol) and HMPA (1.5 mL) in THF (1 mL) were added. . The reaction was stirred at −78 ° C. and allowed to gradually reach ambient temperature overnight and then heated to 35 ° C. to complete the reaction. The reaction was quenched by the addition of ammonium chloride (saturated aqueous solution) and the mixture was extracted with EtOAc (2 × 10 mL). The organics were combined, washed with water, dried (MgSO ₄ ), filtered and concentrated. Silica gel chromatography (98/2 hexane / EtOAc) afforded 0.25 g of (4R) -4,8-dimethylnonanoic acid t-butyl ester.

(4R) -4,8-dimethylnonanoic acid. (4R) -4,8-Dimethylnonanoic acid t-butyl ester in 25 mL of CH ₂ Cl ₂ was treated with TFA (6 mL). The mixture was allowed to reach ambient temperature overnight and stirred. The solvent was removed by rotary evaporation and the mixture was purified by silica gel chromatography (95/5 hexane / EtOAc) to give 0.962 g of (4R) -4,8-dimethylnonanoic acid. m / z 185 (M-).

3- (4R, 8-Dimethyl-nonanoyl) -4 (S) -methyl-5 (R) -phenyl-oxazolidin-2-one. Using a method similar to (4R, 5S) -4-methyl-3- (R) -4-methyl-heptanoyl) -5-oxazolidin-2-one, 3- (4R, 8-dimethyl-nonanoyl)- 4 (S) -methyl-5 (R) -phenyl-oxazolidin-2-one (1.35 g) was obtained. m / z 346.5 (M +).

[4R, 8-Dimethyl-2R- (4R-methyl-2-oxo-5R-phenyl-oxazolidine-3-carbonyl) -nonyl] -carbamic acid benzyl ester. 3- (4 (R), 8-dimethyl-nonanoyl) -4 (S) -methyl-5 (in CH ₂ Cl ₂ (12 mL) and TiCl ₄ (3.04 mL of a 1 M solution in CH ₂ Cl ₂ ) To a solution of R) -phenyl-oxazolidin-2-one (1.05 g, 3.04 mmol) was added diisopropylethylamine (0.55 mL, 3.19 mmol) at −20 ° C. The resulting dark red solution was stirred at −20 ° C. for 30 minutes before a solution of N-methoxymethylbenzylcarbamate (0.652 g, 3.34 mmol) in CH ₂ Cl ₂ (3.5 mL) and TiCl ₄ (3.34 mL). Was added. The mixture was stirred at 0 ° C. for 4 hours. The reaction was quenched by the addition of saturated aqueous ammonium chloride. The mixture was extracted with CH ₂ Cl ₂ (3 × 15 mL). The organics were combined, washed with 1 N HCl, neutralized with NaOH, then washed with brine. The organics were dried (MgSO ₄ ), filtered, concentrated and purified by silica gel chromatography (95/5 hexane / EtOAc) to give 0.555 g of [4R, 8-dimethyl-2R- (4R-methyl- 2-Oxo-5R-phenyl-oxazolidine-3-carbonyl) -nonyl] -carbamic acid benzyl ester was obtained.

2 (R)-(benzyloxycarbonylamino-methyl) -4 (R), 8-dimethyl-nonanoic acid. Using a procedure similar to that of (S) -2 ((R) -2-methyl = pentyl) succinic acid t-butyl ester, 0.198 g of 2 (R)-(benzyloxycarbonylamino-methyl) -4 (R), 8-dimethyl-nonanoic acid was obtained.

2-Aminomethyl-4,8-dimethylnonanoic acid. 2 (R)-(benzyloxycarbonylamino-methyl) -4 (R), 8-dimethyl-nonanoic acid (0.148 g, 0.566 mmol) was treated with hydrogen in the presence of 20% Pd / C and filtered. And purification by silica gel chromatography (85/15 CH ₂ Cl ₂ / MeOH) gave 0.082 g of 2-aminomethyl-4,8-dimethylnonanoic acid. m / z 216.3 (M +).

Example 10 2-Aminomethyl-4,4,8-trimethyl-nonanoic acid
2,2,6-Trimethyl-heptanoic acid methyl ester. To diisopropylamine (1.54 mL, 11.03 mmol) in THF (22 mL) was added nBuLi (6.89 mL of a 1.6 M solution in hexane) at −78 ° C. The solution was stirred at −78 ° C. for 30 minutes before methyl isobutyrate (0.97 mL, 8.48 mmol) was added. The mixture was stirred at −78 ° C. for 2 hours, then 1-iodo-4-methylpentane (1.8 g, 8.48 mmol) and DMPU (0.55 mL, 4.24 mmol) in THF (6 mL) were added. The reaction was stirred at −78 ° C. and allowed to gradually reach ambient temperature over 16 hours. The reaction was quenched by the addition of ammonium chloride (saturated aqueous solution) and the mixture was extracted with EtOAc (2 × 10 mL). The organics were combined, washed with water, dried (MgSO ₄ ), filtered and concentrated. Silica gel chromatography (99/1 hexane / EtOAc) gave 1.57 g of 2,2,6-trimethylheptanoic acid methyl ester.

2,2,6-trimethylheptan-1-ol. 2,2,6-Trimethylheptanoic acid methyl ester (1.97 g, 10.6 mmol) was taken up in toluene (65 mL) and cooled to -78 ° C. DiBALH (12.7 mL of 1 N solution in toluene) was added dropwise. After 45 minutes, 1.5 mL of DiBALH was added. After 2 hours, the reaction was quenched by adding 15 mL of MeOH at −78 ° C. The mixture was warmed to ambient temperature and then cooled back to -78 ° C for the addition of 10 mL of 1 N HCl. The mixture was extracted with EtOAc (3 x 15 mL). The combined organics were washed with brine, dried (MgSO ₄ ), filtered and concentrated. The residual oil was purified by silica gel chromatography (95/5 hexane / EtOAc) to give 2,2,6-trimethyl-heptan-1-ol (0.88 g). m / z 159 (M +).

2,2,6-trimethyl-heptanal. Pyridinium chlorochromate (PCC, 4.17 g, 19.4 mmol) was combined with neutral alumina (14.6 g) in CH ₂ Cl ₂ and stirred at ambient temperature for 15 minutes. The alcohol was diluted in CH ₂ Cl ₂ and the mixture was stirred at ambient temperature for 2 hours. The solution was filtered through a pad of silica and the solid was washed with CH ₂ Cl ₂ . The filtrate was evaporated to give 1.05 g of m / z 157 (M +) 2,2,6-heptanal, which was continued without further purification.

2-Cyano-4,4,8-trimethyl-non-2-enoic acid benzyl ester. To a mixture of 2,2,6-trimethyl-heptanal (1.05 g, 6.73 mmol), piperidine (0.19 mL, 2.01 mmol) and benzyl cyanoacetate (1.29 g, 7.4 mmol) in toluene (50 mL) was added glacial acetic acid ( 0.72 g, 12.1 mmol) was added. The flask was equipped with a Dean Stark and wrap and the mixture was heated at reflux for 18 hours. The mixture was cooled and treated with dilute HCl and the layers were separated. The organics were washed with saturated sodium bicarbonate solution followed by brine, dried (MgSO ₄ ), filtered and concentrated. The residual oil was purified by silica gel chromatography (98/2 hexane / EtOAc) to give 1.3 g of 2-cyano-4,4,8-trimethyl-non-2-enoic acid benzyl ester. m / z 314 (M +).

2-Aminomethyl-4,4,8-trimethyl-nonanoic acid. 2-Cyano-4,4,8-trimethyl-non-2-enoic acid benzyl ester (1.3 g, 4.14 mmol) in THF (50 mL) was treated with hydrogen in the presence of 20% Pd / C. A mixture of cyanic acid and cyanomethyl ester was obtained. The mixture was purified by silica gel chromatography to give 278 mg of 80105 × 41-1-2. The acid was then treated with hydrogen in the presence of Raney Ni in MeOH / NH ₄ OH to give 0.16 g of 2-aminomethyl-4,4,8-trimethyl-nonanoic acid. m / z 230.3 (M +).

Example 11 2-Aminomethyl-4-ethyl-octanoic acid Using a method similar to that of 2-aminomethyl-4,4,8-trimethyl-nonanoic acid, 2-ethylhexanal to 2-aminomethyl-4-ethyl- Octanoic acid was prepared. m / z 202.1 (M +).

Example 12 2-Aminomethyl-4-ethyl-8-methyl- nonanoic acid 2,6-di-t-butyl- using a method similar to that of 2-aminomethyl-4,4,8-trimethyl-nonanoic acid 2-Aminomethyl-8-methyl-nonanoic acid was prepared from 4-methylphenylcyclopropylcarboxylate. m / z 230.2 (M +).

Example 13 3-amino-2- [1- (4-methyl-pentyl) -cyclopropylmethyl] -propionic acid 2-aminomethyl-4,4,8-trimethyl-nonanoic acid 2-Aminomethyl-8-methyl-nonanoic acid was prepared from 1,6-di-t-butyl-4-methylphenylcyclopropylcarboxylate. m / z 228.2 (M +).

Example 14 2-Aminomethyl-4-ethyl-hexanoic acid Using a method similar to that of 2-aminomethyl-4,8-dimethyl-nonanoic acid, 4-ethylhexanoic acid to 2-aminomethyl-4-ethyl-hexane The acid was prepared. m / z 174.1.

Example 15. 3 (S) -amino-3,5-dimethyl-heptanoic acid
2-Methyl-propane-2 (S) -sulfinic acid (1,3-dimethyl-pentylidene) -amide. (S)-(−)-2-methyl-2-propanesulfonamide (500 mg, 4.1 mmol), 4-methyl-2-hexanone (470 mg, 4.1 mmol) and titanium (IV) ethoxide (1.7 mL, 8.3) mmol) was heated at reflux for 18 hours. The reaction mixture was poured into 20 mL brine with rapid stirring. The resulting solution was filtered through celite and the organic layer was separated. The aqueous layer was extracted with ethyl acetate (2 × 20 mL). The combined organics were dried (MgSO ₄ ), filtered and concentrated. The resulting oil was purified by silica gel chromatography (25% EtOAc in hexanes) to yield 575 mg of 2-methyl-propane-2 (S) -sulfinic acid (1,3-dimethyl-pentylidene) -amide as a yellow color. Obtained as an oil.

3,5-Dimethyl-3- (2-methyl-propane-2 (S) -sulfinylamino) -heptanoic acid methyl ester. Methyl acetate (0.41 mL, 5.1 mmol) was added dropwise to a −78 ° C. solution of lithium bis (trimethylsilyl) amide (1 M solution in THF 5.1 mL) in THF (6 mL). After stirring for 20 minutes, a solution of chlorotitanium triisopropoxide (2.5 mL, 10 mmol) in THF (3 mL) was added dropwise. After 1 hour, 2-methyl-propane-2 (S) -sulfinic acid (1,3-dimethyl-pentylidene) -amide (560 mg, 2.6 mmol) in THF (3 mL) was added dropwise at -78 ° C. The reaction was stirred at −78 ° C. for 5 hours, then quenched by addition of 10 mL ammonium chloride and allowed to warm to room temperature. The mixture was diluted with 10 mL water and filtered. The aqueous layer was extracted with ethyl acetate (2 × 20 mL). The combined organics were washed with brine, dried (Na ₂ SO ₄ ), filtered and concentrated. The resulting oil was purified by silica gel chromatography (30% EtOAc in hexanes) to give 360 mg of 3,5-dimethyl-3- (2-methyl-propane-2 (S) -sulfinylamino) -heptanoic acid. The methyl ester was obtained.

3 (S) -amino-3,5-dimethyl-heptanoic acid. 3,5-Dimethyl-3- (2-methyl-propane-2 (S) -sulfinylamino) -heptanoic acid methyl ester (360 mg, 1.2 mmol) in 6 N HCl (2 mL) and dioxane (2 mL) Dissolved and heated at 100 ° C. for 6 hours. The mixture was cooled to room temperature, diluted with water and extracted with EtOAc (15 mL). The organics were purified by ion exchange chromatography to give 3 (S) -amino-3,5-dimethyl-heptanoic acid (270 mg) followed by silica gel chromatography (70: 25: 5 CH ₂ Cl ₂ / Re-purification with MeOH / NH ₄ OH) gave 203 mg of 3 (S) -amino-3,5-dimethyl-heptanoic acid as a white solid. _{m / z174 (C 9 H 19} NO 2 + H).

Example 16 3 (S) -amino-3,5-dimethyl-nonanoic acid 3 (S) -amino-3,5 using a method similar to that of 3 (S) -amino-3,5-dimethyl-heptanoic acid -Dimethyl-nonanoic acid was prepared. _{m / z202.1 (C 11 H 23} NO 2 + H).

Example 17. 3 (S) -amino-3,5-dimethyl-octanoic acid 3 (S) -amino-3,5 using a method similar to that of 3 (S) -amino-3,5-dimethyl-heptanoic acid -Dimethyl-nonanoic acid was prepared. _{m / z188.1 (C 10 H 21} NO 2 + H).

Claims (12)

Acupuncture, smoking cessation, withdrawal from addictive substances and dependence, spasticity, muscle spasticity, hypotonia with paralysis, postherpetic neuralgia, chronic headache, low back pain, surgical pain, cartilage damage, osteoarthritis A method of treatment, wherein a mammal in need of such treatment is provided with a therapeutically effective amount of Formula I:

Wherein R ₁ is hydrogen or (C ₁ -C ₆ ) alkyl optionally substituted with 1 to 5 fluorine atoms;
R ₂ is hydrogen or (C ₁ -C ₆ ) alkyl optionally substituted with 1 to 5 fluorine atoms; or R ₁ and R ₂ together with the carbon to which they are attached. Forming a 3-6 membered cycloalkyl ring;
R ₃ is (C ₁ -C ₆ ) alkyl, (C ₃ -C ₆ ) cycloalkyl, (C ₃ -C ₆ ) cycloalkyl- (C ₁ -C ₃ ) alkyl, phenyl, phenyl- (C _1- C ₃ ) alkyl, pyridyl, pyridyl- (C ₁ -C ₃ ) alkyl, phenyl-N (H)-, or pyridyl-N (H)-(wherein each alkyl moiety is 1-5 And optionally substituted with 0 to 3 fluorine atoms, and said phenyl and said pyridyl, and said phenyl- (C ₁ -C ₃ ) alkyl and said pyridyl- (C ₁ -C ₃₎ phenyl and pyridyl moieties of alkyl, respectively, chloro, fluoro, amino, nitro, cyano, (C ₁ -C ₃₎ alkylamino, optionally (C ₁ -C ₃₎ alkyl (1-3 fluorine atoms ), In and (C ₁ -C ₃₎ 1-3 substituents independently selected from alkoxy (optionally substituted with 1 to 3 fluorine atoms), preferably 0 to 2 substituents Can be optionally substituted);
R ₄ is hydrogen or (C ₁ -C ₆ ) alkyl (optionally substituted with 1 to 5 fluorine atoms);
R ₅ is hydrogen or (C ₁ -C ₆ ) alkyl (optionally substituted with 1 to 5 fluorine atoms); and R ₆ is hydrogen or (C ₁ -C ₆ ) alkyl. )
Or a pharmaceutically acceptable salt of such a compound.   A method of treating cognition in a neurodegenerative disorder such as Parkinson's disease (PD), Huntington's disease (HD), Alzheimer's disease and fibromyalgia by enhancing sleep in a mammal, such as a human, comprising such a disorder or symptom. A method comprising administering to said mammal an amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof that is effective to treat.   A method of treating a disorder or symptom selected from the group consisting of sleep disorders in mammals, such as humans, such as non-resting leg syndrome, jet lag, periodic limb movement disorders and sleep building alterations, A method comprising administering to said mammal an amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof that is effective to treat the disease.   A method of promoting weight gain in a mammal, eg, a mammal having a disorder or symptom selected from anorexia, cancer, advanced age and / or weakness in a human, and is effective in treating such disorder or symptom A method comprising administering to said mammal an amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.   A method of treating a disorder or symptom selected from social anxiety disorder and fear of flying in a mammal, eg, a human, in an amount effective to treat such disorder or symptom. Or administering a pharmaceutically acceptable salt thereof to said mammal. The compound or pharmaceutically acceptable salt of such a compound is of the formula IA:

Wherein R ₁ is hydrogen or (C ₁ -C ₆ ) alkyl optionally substituted with 1 to 5 fluorine atoms;
R ₂ is hydrogen or (C ₁ -C ₆ ) alkyl optionally substituted with 1 to 5 fluorine atoms; and R ₃ is (C ₁ -C ₆ ) alkyl, (C ₃ -C ₆₎ cycloalkyl, (C ₃ -C ₆₎ cycloalkyl - (C ₁ ~C ₃₎ alkyl, phenyl, phenyl - (C ₁ ~C ₃₎ alkyl, pyridyl, pyridyl - (C ₁ ~C ₃₎ alkyl, Phenyl-N (H)-, or pyridyl-N (H)-, wherein the alkyl moieties are each optionally substituted with 1 to 5 fluorine atoms, preferably 0 to 3 fluorine atoms. And the phenyl and pyridyl, and the phenyl and pyridyl moieties of the phenyl- (C ₁ -C ₃ ) alkyl and pyridyl- (C ₁ -C ₃ ) alkyl are chloro, fluoro, amino, Nitro, cyano, ( In ₁ -C ₃₎ alkylamino, (C ₁ -C ₃₎ alkyl (optionally substituted with 1 to 3 fluorine atoms), and (C ₁ -C ₃₎ alkoxy (1-3 fluorine atoms Optionally substituted) with 1 to 3 substituents independently selected from, preferably 0 to 2 substituents).
However, when R ₁ is hydrogen, R ₂ is not hydrogen)
The method of claim 1, comprising: A compound or pharmaceutically acceptable salt of such a compound is of formula II:

Wherein R ₁ is hydrogen or (C ₁ -C ₆ ) alkyl optionally substituted with 1 to 5 fluorine atoms;
R ₂ is hydrogen or (C ₁ -C ₆ ) alkyl optionally substituted with 1 to 5 fluorine atoms; and R ₃ is (C ₁ -C ₆ ) alkyl, (C ₃ -C ₆₎ cycloalkyl, (C ₃ -C ₆₎ cycloalkyl - (C ₁ ~C ₃₎ alkyl, phenyl, phenyl - (C ₁ ~C ₃₎ alkyl, pyridyl, pyridyl - (C ₁ ~C ₃₎ alkyl, Phenyl-N (H)-, or pyridyl-N (H)-, wherein the alkyl moieties are each optionally substituted with 1 to 5 fluorine atoms, preferably 0 to 3 fluorine atoms. And the phenyl and pyridyl, and the phenyl and pyridyl moieties of the phenyl- (C ₁ -C ₃ ) alkyl and pyridyl- (C ₁ -C ₃ ) alkyl are chloro, fluoro, amino, Nitro, cyano, ( In ₁ -C ₃₎ alkylamino, (C ₁ -C ₃₎ alkyl (optionally substituted with 1 to 3 fluorine atoms), and (C ₁ -C ₃₎ alkoxy (1-3 fluorine atoms Optionally substituted) with 1 to 3 substituents independently selected from, preferably 0 to 2 substituents).
However, when R ₁ is hydrogen, R ₂ is not hydrogen)
The method of claim 1, comprising: The compound or pharmaceutically acceptable salt of such a compound is of formula IA-1:

Wherein R ₃ is (C ₁ -C ₆ ) alkyl, (C ₃ -C ₆ ) cycloalkyl, (C ₃ -C ₆ ) cycloalkyl- (C ₁ -C ₃ ) alkyl, phenyl, phenyl- (C ₁ -C ₃ ) alkyl, pyridyl, pyridyl- (C ₁ -C ₃ ) alkyl, phenyl-N (H)-, or pyridyl-N (H)-(wherein the alkyl moieties are each It may be optionally substituted with 1 to 5 fluorine atoms, preferably 0 to 3 fluorine atoms, and said phenyl and said pyridyl, and said phenyl- (C ₁ -C ₃ ) alkyl and said pyridyl- ( C ₁ -C ₃₎ phenyl and pyridyl moieties of alkyl, respectively, chloro, fluoro, amino, nitro, cyano, (C ₁ -C ₃₎ alkylamino, (C ₁ -C ₃₎ alkyl (1-3 Optionally substituted with fluorine atoms That), and (in C ₁ -C ₃₎ 1-3 substituents selected from alkoxy (optionally substituted with 1 to 3 fluorine atoms), preferably 0 to 2 substituents Can be optionally substituted))
The method of claim 6, comprising: The compound or pharmaceutically acceptable salt of such a compound is of formula IIA:

Wherein R ₃ is (C ₁ -C ₆ ) alkyl, (C ₃ -C ₆ ) cycloalkyl, (C ₃ -C ₆ ) cycloalkyl- (C ₁ -C ₃ ) alkyl, phenyl, phenyl- (C ₁ -C ₃ ) alkyl, pyridyl, pyridyl- (C ₁ -C ₃ ) alkyl, phenyl-N (H)-, or pyridyl-N (H)-(wherein the alkyl moieties are each It may be optionally substituted with 1 to 5 fluorine atoms, preferably 0 to 3 fluorine atoms, and said phenyl and said pyridyl, and said phenyl- (C ₁ -C ₃ ) alkyl and said pyridyl- ( C ₁ -C ₃₎ phenyl and pyridyl moieties of alkyl, respectively, chloro, fluoro, amino, nitro, cyano, (C ₁ -C ₃₎ alkylamino, (C ₁ -C ₃₎ alkyl (1-3 Optionally substituted with fluorine atoms That), and (in C ₁ -C ₃₎ 1-3 substituents selected from alkoxy (optionally substituted with 1 to 3 fluorine atoms), preferably 0 to 2 substituents Can be optionally substituted))
The method of claim 7, comprising: The compound or pharmaceutically acceptable salt of such a compound is of formula IA-2:

Wherein R ₁ is hydrogen or (C ₁ -C ₆ ) alkyl optionally substituted with 1 to 5 fluorine atoms;
R ₂ is hydrogen or (C ₁ -C ₆ ) alkyl optionally substituted with 1 to 5 fluorine atoms; and R ₃ is (C ₁ -C ₆ ) alkyl, (C ₃ -C ₆₎ cycloalkyl, (C ₃ -C ₆₎ cycloalkyl - (C ₁ ~C ₃₎ alkyl, phenyl, phenyl - (C ₁ ~C ₃₎ alkyl, pyridyl, pyridyl - (C ₁ ~C ₃₎ alkyl, Phenyl-N (H)-, or pyridyl-N (H)-, wherein the alkyl moieties are each optionally substituted with 1 to 5 fluorine atoms, preferably 0 to 3 fluorine atoms. And the phenyl and pyridyl, and the phenyl and pyridyl moieties of the phenyl- (C ₁ -C ₃ ) alkyl and pyridyl- (C ₁ -C ₃ ) alkyl are chloro, fluoro, amino, Nitro, cyano, ( In ₁ -C ₃₎ alkylamino, (C ₁ -C ₃₎ alkyl (optionally substituted with 1 to 3 fluorine atoms), and (C ₁ -C ₃₎ alkoxy (1-3 fluorine atoms Optionally substituted) with 1 to 3 substituents independently selected from, preferably 0 to 2 substituents).
However, when R ₁ is hydrogen, R ₂ is not hydrogen)
The method of claim 6, comprising: The compound or pharmaceutically acceptable salt thereof is of formula III:

Wherein R ₃ is (C ₁ -C ₆ ) alkyl, (C ₃ -C ₆ ) cycloalkyl, (C ₃ -C ₆ ) cycloalkyl- (C ₁ -C ₃ ) alkyl, phenyl, phenyl- (C ₁ -C ₃ ) alkyl, pyridyl, pyridyl- (C ₁ -C ₃ ) alkyl, phenyl-N (H)-, or pyridyl-N (H)-(wherein the alkyl moieties are each It may be optionally substituted with 1 to 5 fluorine atoms, preferably 0 to 3 fluorine atoms, and said phenyl and said pyridyl, and said phenyl- (C ₁ -C ₃ ) alkyl and said pyridyl- ( C ₁ -C ₃₎ phenyl and pyridyl moieties of alkyl, respectively, chloro, fluoro, amino, nitro, cyano, (C ₁ -C ₃₎ alkylamino, (C ₁ -C ₃₎ alkyl (1-3 Optionally substituted with fluorine atoms That), and (in C ₁ -C ₃₎ 1-3 substituents selected from alkoxy (optionally substituted with 1 to 3 fluorine atoms), preferably 0 to 2 substituents Can be optionally substituted))
The method of claim 1, comprising: The compound or a pharmaceutically acceptable salt of such a compound is of formula IV:

Wherein R ₁ is hydrogen or (C ₁ -C ₆ ) alkyl optionally substituted with 1 to 5 fluorine atoms; and R ₃ is (C ₁ -C ₆ ) alkyl, ( C ₃ -C ₆₎ cycloalkyl, (C ₃ ~C ₆₎ cycloalkyl - (C ₁ ~C ₃₎ alkyl, phenyl, phenyl - (C ₁ ~C ₃₎ alkyl, pyridyl, pyridyl - (C ₁ -C ₃ ) alkyl, phenyl-N (H)-, or pyridyl-N (H)-, wherein each alkyl moiety is 1 to 5 fluorine atoms, preferably 0 to 3 fluorine atoms And the phenyl and pyridyl moieties of said phenyl and said pyridyl, and said phenyl- (C ₁ -C ₃ ) alkyl and said pyridyl- (C ₁ -C ₃ ) alkyl are each chloro, Fluoro, amino, nitro, Bruno, (C ₁ -C ₃₎ alkylamino, (C ₁ -C ₃₎ alkyl (optionally substituted with 1 to 3 fluorine atoms), and (C ₁ -C ₃₎ alkoxy (1-3 Optionally substituted with 1 to 3 substituents, preferably 0 to 2 substituents)))
The method of claim 1, comprising: